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New study finds triple-negative breast cancer tumors with an increase in immune cells have lower risk of recurrence after surgery

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By Kelley Luckstein

A new multicenter, international study suggests that people who have early-stage  triple-negative breast cancer  (TNBC) and high levels of immune cells within their tumors may have a lower risk of recurrence and better survival rates even when not treated with chemotherapy. The  study  was published today in the Journal of American Medical Association (JAMA).

TNBC is a breast cancer subtype that does not respond to drugs that target the estrogen receptor or the HER2 protein. It grows rapidly, is more likely to spread beyond the breast before diagnosis and is more likely to recur than other breast cancers. TNBC represents about 15% of all breast cancers and is more common in younger people and in women of African American, Hispanic and Indian descent. Immune cells, also known as tumor-infiltrating lymphocytes, or TILs, are naturally existing immune system cells that can move from the bloodstream into a tumor and can recognize and destroy cancer cells.

"This is an important finding because it highlights that the abundance of TILs in breast tissue is a prognostic biomarker in people with early-stage triple-negative breast cancer, even when chemotherapy is not administered," says  Roberto Leon-Ferre, M.D. , a breast medical oncologist at  Mayo Clinic Comprehensive Cancer Center  and first author of the study. "The study's findings may inspire future clinical trials to explore whether patients with a favorable prognosis (high TILs) can avoid intensive chemotherapy regimens."

"This meta-analysis confirms robustly the prognostic value of TILs that we have previously reported in TNBC patients treated with chemotherapy and expands it to patients treated without chemotherapy," says Sarah Flora Jonas, Ph.D., a statistician at  Gustave Roussy  and co-first author of the study. "Future studies may allow the use of this biomarker along with standard clinicopathological factors to inform treatment decisions in TNBC patients."

"Of interest, the first report suggesting that an increased number of immune cells being associated with better prognosis in breast cancer patients was described by doctors at Mayo Clinic more than 100 years ago," says Roberto Salgado, M.D., co-chair of the International Immuno-Oncology Biomarker Working Group; co-lead of the study; and pathologist from the Peter MacCallum Cancer Centre, Melbourne, Australia, and ZAS Hospitals, Antwerp, Belgium. "It took a global effort and a century later to reexamine this biomarker and bring it closer to application in patient care."

"TILs are not currently measured or reported in the routine examination of tissue samples of breast cancer," says co-senior author,  Matthew Goetz, M.D. , a medical oncologist at Mayo Clinic Comprehensive Cancer Center and the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D. "While prior studies have focused on measuring TILs in people treated with chemotherapy, this is the largest study to comprehensively demonstrate that the presence of TILs influences the natural behavior of breast cancer in people who have surgery and/or radiation with no additional medical treatment."

For this study, Mayo Clinic and Gustave Roussy researchers, in collaboration with the International Immuno-Oncology Biomarker Working Group, led 11 additional groups to collect data on 1,966 participants with early-stage TNBC who only underwent surgery with or without radiation therapy but did not receive chemotherapy. The participants had been followed for a median of 18 years. The results showed that higher levels of TILs in breast cancer tissue were associated with lower recurrence rates among participants with early-stage TNBC.

"Five years after surgery, 95% of participants with small tumors, stage 1 TNBC, and whose tumors had high TILs were alive, compared to 82% of patients whose tumors had low TILs. Importantly, the breast cancer recurrence rate was significantly lower among patients whose tumors had high TILs," says co-senior author,  Stefan Michiels, Ph.D. , head of Oncostat team, Gustave Roussy, Inserm U1018, University Paris-Saclay. "With nearly 2,000 participants involved in the study, we have now assembled the largest international cohort across three continents of people with TNBC in which the primary treatment was surgery without chemotherapy."

"The results of this study could lead to a recommendation to include TILs in the pathology reports of early-stage TNBC worldwide, as it has the potential to inform clinicians and patients when they discuss treatment options," says Dr. Salgado.

Furthermore, this biomarker would only require a visual evaluation by a pathologist looking through a microscope, meaning there are no additional costs associated with identifying the presence of immune cells. This could be particularly beneficial to regions with limited resources, adds Dr. Leon-Ferre.

Most people with early-stage TNBC undergo chemotherapy either before or after surgery, including people with stage 1 breast cancer. Most people receive multiple chemotherapy drugs in combination, which can cause significant side effects. Currently, the main factors considered to determine the course of chemotherapy treatment for each person are the tumor size and whether the cancer has spread to the lymph nodes. However, the authors identified that the number of TILs further influences the risk of future recurrence.

The researchers plan to evaluate TILs as biomarkers in prospective clinical trials evaluating chemotherapy selection based on TIL levels. Ongoing efforts to conduct additional research with other potential biomarkers are underway.

For a complete list of authors, disclosures and funding, see the full paper  here .

Learn more about breast cancer and find a clinical trial at Mayo Clinic.

Join the Breast Cancer Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

• Understanding triple-negative breast cancer and its treatment
• 17-gene signature linked to remission after triple-negative breast cancer treatment

A version of this article was originally published as a press release on the Mayo Clinic News Network .

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New cancer treatment may reawaken the immune system

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Immunotherapy is a promising strategy to treat cancer by stimulating the body’s own immune system to destroy tumor cells, but it only works for a handful of cancers. MIT researchers have now discovered a new way to jump-start the immune system to attack tumors, which they hope could allow immunotherapy to be used against more types of cancer.

Their novel approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back in the tumor. When delivered along with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that spurs the T cells into action.

“When you create cells that have DNA damage but are not killed, under certain conditions those live, injured cells can send a signal that awakens the immune system,” says Michael Yaffe, who is a David H. Koch Professor of Science, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research.

In mouse studies, the researchers found that this treatment could completely eliminate tumors in nearly half of the mice.

Yaffe and Darrell Irvine, who is the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering, and an associate director of the Koch Institute, are the senior authors of the study, which appears today in Science Signaling . MIT postdoc Ganapathy Sriram and Lauren Milling PhD ’21 are the lead authors of the paper.

T cell activation

One class of drugs currently used for cancer immunotherapy is checkpoint blockade inhibitors, which take the brakes off of T cells that have become “exhausted” and unable to attack tumors. These drugs have shown success in treating a few types of cancer but do not work against many others.

Yaffe and his colleagues set out to try to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in hopes that the chemotherapy could help stimulate the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the immune system’s attention.

Several clinical trials combining chemotherapy and immunotherapy drugs are underway, but little is known so far about the best way to combine these two types of treatment.

The MIT team began by treating cancer cells with several different chemotherapy drugs, at different doses. Twenty-four hours after the treatment, the researchers added dendritic cells to each dish, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill the cancer cells. To their surprise, they found that most of the chemotherapy drugs didn’t help very much. And those that did help appeared to work best at low doses that didn’t kill many cells.

The researchers later realized why this was so: It wasn’t dead tumor cells that were stimulating the immune system; instead, the critical factor was cells that were injured by chemotherapy but still alive.

“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for cancer treatment,” Yaffe says. “We showed that if you treated tumor cells in a dish, when you injected them back directly into the tumor and gave checkpoint blockade inhibitors, the live, injured cells were the ones that reawaken the immune system.”

The drugs that appear to work best with this approach are drugs that cause DNA damage. The researchers found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send out distress signals that provoke T cells to leap into action and destroy not only those injured cells but any tumor cells nearby.

“Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system, a theory pioneered by Polly Matzinger at NIH in the 1990s, though still not universally accepted,” Yaffe says.  

Tumor elimination

In studies of mice with melanoma and breast tumors, the researchers showed that this treatment eliminated tumors completely in 40 percent of the mice. Furthermore, when the researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.

The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but they found this was not effective because the chemotherapy drugs also harmed T cells and other immune cells near the tumor. Also, injecting the injured cells without checkpoint blockade inhibitors had little effect.

“You have to present something that can act as an immunostimulant, but then you also have to release the preexisting block on the immune cells,” Yaffe says.

Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, but more study is needed first to determine which drugs, and at which doses, would be most beneficial for different types of tumors. The researchers are also further investigating the details of exactly how the injured tumor cells stimulate such a strong T cell response.

The research was funded, in part, by the National Institutes of Health, the Mazumdar-Shaw International Oncology Fellowship, the MIT Center for Precision Cancer Medicine, and the Charles and Marjorie Holloway Foundation.

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Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

• Ignacio Heras-Murillo
• Irene Adán-Barrientos
• David Sancho

Molecular profile of bladder cancer progression to clinically aggressive subtypes

In this Review, the authors describe the molecular profile of bladder cancer progression associated with the subtypes of this disease and comment on their potential diagnostic, prognostic and therapeutic importance.

• Charles C. Guo
• Sangkyou Lee
• Bogdan Czerniak

Multiplex protein imaging in tumour biology

In this Review, de Souza et al. discuss how advances in the ability to image protein markers at high-plex, at single-cell and even subcellular resolution, are expanding our understanding of tumour biology and clinical outcomes, and outline the future promise of combining such multiplex protein imaging methods with other forms of spatial omics.

• Natalie de Souza
• Bernd Bodenmiller

The yin and yang of chromosomal instability in prostate cancer

Chromosomal instability is a hallmark of advanced prostate cancer. In this Review, the authors discuss the biological causes and paradoxical consequences of chromosomal instability, its potential clinical role in the stratification of prostate cancer aggressiveness and the development of novel treatment strategies.

• Marc Carceles-Cordon
• Jacob J. Orme
• Veronica Rodriguez-Bravo

Management of patients with muscle-invasive bladder cancer with clinical evidence of pelvic lymph node metastases

Muscle-invasive bladder cancer with clinically positive pelvic lymph nodes is a particular situation at the interface between localized and metastatic disease. In this Review, the authors discuss the advances and challenges of currently available strategies for the diagnosis and treatment of patients with muscle-invasive bladder cancer with clinically positive pelvic lymph nodes.

• Elisabeth Grobet-Jeandin
• Louis Lenfant
• Thomas Seisen

The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men

African American men are disproportionately affected by prostate cancer in the USA. In this Review, the authors discuss the complex interplay of modifiable risk factors that might underlie the glaring prostate cancer disparities observed.

• Jabril R. Johnson
• Nicole Mavingire
• Rick A. Kittles

Extrachromosomal DNA in cancer

Extrachromosomal DNA (ecDNA) is now accepted as a major contributor to cancer pathogenesis. In this Review, Yan, Mischel and Chang highlight the recent advancements in ecDNA research, providing new insights into the biogenesis and maintenance of ecDNA, as well as its role in altering gene expression and promoting tumour heterogeneity.

• Xiaowei Yan
• Paul Mischel
• Howard Chang

Natural killer cell therapies

This Review explores in detail the complexity of NK cell biology in humans and highlights the role of these cells in cancer immunity.

• Eric Vivier
• Lucas Rebuffet
• Valeria R. Fantin

Clinical and translational attributes of immune-related adverse events

Suijkerbuijk et al. summarize the clinical manifestation and classification of immune-related adverse events, discuss the immunopathogenesis of immune-related adverse events and provide key insights into their management and future therapeutic directions.

• Karijn P. M. Suijkerbuijk
• Mick J. M. van Eijs
• Alexander M. M. Eggermont

Translating p53-based therapies for cancer into the clinic

Although p53 was once considered undruggable, in this Review, Peuget et al. discuss the progress made in targeting p53 as a form of cancer therapy with approaches ranging from restoration of mutant p53 function to inhibition of the negative regulator of p53, MDM2, as well as newer strategies, including p53-based mRNA vaccines and antibodies.

• Sylvain Peuget
• Xiaolei Zhou
• Galina Selivanova

Aneuploidy and complex genomic rearrangements in cancer evolution

Van Loo and colleagues review the mechanistic underpinnings of large genomic alterations and their roles in tumor development and evolution.

• Toby M. Baker
• Peter Van Loo

FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress

Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.

• Jessica D. Tischler
• Hiroshi Tsuchida
• Richard O. Adeyemi

BRAF — a tumour-agnostic drug target with lineage-specific dependencies

Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAF V600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF -mutant cancers.

• Aphrothiti J. Hanrahan
• David B. Solit

News & Commentary

Do cutting-edge CAR-T-cell therapies cause cancer? What the data say

Regulators have identified around 30 cases of cancer linked to this blockbuster treatment. But is CAR T to blame? The hunt is on for answers.

• Cassandra Willyard

Adjuvant pembrolizumab improves overall survival in patients with RCC

• Peter Sidaway

PRMT9 inhibition sparks immune responses in AML

Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.

• Antonella Santoro
• Raffaella Di Micco

Experimental evolution of cancer chromosomal changes

Experimental genome evolution of normal human cells reveals an intrinsic propensity to develop cancer-associated chromosomal alterations.

• Molly A. Guscott
• Sarah E. McClelland

Sarcoma ecotypes determine immunotherapy benefit

Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.

• Johanna Wagner
• Stefan Fröhling

Adjuvant alectinib improves outcomes in ALK -mutant NSCLC

• Diana Romero

NALIRIFOX for metastatic pancreatic adenocarcinoma: hope or hype?

The FDA has approved nanoliposomal irinotecan, 5-fluorouracil, leucovorin and oxaliplatin (NALIRIFOX) for patients with metastatic pancreatic adenocarcinoma on the basis of results from the NAPOLI 3 trial, in which this four-drug regimen improved overall survival relative to a doublet regimen. Here we discuss how, in the context of prior results from the PRODIGE 4 trial testing 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (modified FOLFIRINOX), NALIRIFOX does not seem to raise the bar, but rather exposes patients and health-care systems to financial toxicities.

• Christopher Nevala-Plagemann
• Ignacio Garrido-Laguna

From AACR 2024

Mini-colon and brain ‘organoids’ shed light on cancer and other diseases

Tiny 3D structures made from human stem cells sometimes offer insights that animal models cannot.

• Sara Reardon

Tonic-ing emissions and compatibility to turbocharge CAR-T

Optimization of energy and carbon–nitrogen allocation maximizes the proliferation and functionality of chimeric antigen receptor (CAR)-T cells. Lakhani et al. report that tonic signalling elements (scFvs) affect CAR-T cell metabolic fitness in an antigen-independent manner. A modest carbon–nitrogen emission (overflow) and resilient metabolic phenotype (compatibility) are associated with effective CAR-T cell therapy.

• Haopeng Wang
• Yuwei Huang
• Ruoning Wang

Bioengineered ‘mini-colons’ shed light on cancer progression

Cells grown on a 3D scaffold have generated a ‘mini-colon’ that mimics key features of the organ. Controlled expression of cancer-associated genes in the system offers a way to examine tumour formation over space and time.

• Nicolò Riggi
• Felipe de Sousa e Melo

Tumours form without genetic mutations

Researchers find that brief and reversible inhibition of a gene-silencing mechanism leads to irreversible tumour formation in fruit flies, challenging the idea that cancer is caused only by permanent changes to DNA.

• Anne-Kathrin Classen

Lighting the torch: intratumoural T cell-to-stroma enrichment score as a predictor of immunotherapy response in urothelial carcinoma

T cell infiltration in the tumour microenvironment (TME) is a prerequisite for sustained antitumour immune responses. However, identifying predictive biomarkers that quantify T cell infiltration and the presence of proinflammatory TMEs associated with immune-checkpoint inhibitor (ICI) response for clinical implementation has proved challenging. Here, we highlight a study that validates a T cell-to-stroma enrichment score generated from RNA sequencing data as a novel biomarker for ICI response in patients with urothelial carcinoma.

• David H. Aggen
• Jonathan E. Rosenberg

A CAF subpopulation promotes LVI in early-stage bladder cancer

• Maria Chiara Masone

The case for centralization of care in penile cancer — respecting geographical needs

Centralization of care for penile cancer has been underscored in the 2023 updated EAU–ASCO guidelines. Expertise consolidation enhances patient care, addressing penile cancer complexities from diagnosis to treatment. Centralization initiatives, like the European Reference Networks, and dedicated scientific societies have crucial roles in guiding centralized care pathways to ultimately improve patient outcomes.

• Giuseppe Basile
• Andrea Necchi
• Peter A. S. Johnstone

Targeting immunogenic cell stress and death for cancer therapy

Immunogenic cell death (ICD) is crucial for the elicitation of anticancer immune responses by therapy, but the successful development of ICD-inducing treatments is hindered by various obstacles. This Review provides an overview of the core mechanisms of ICD, discusses obstacles to the development of novel ICD modulators and assesses established and innovative therapeutic approaches for ICD induction.

• Lorenzo Galluzzi
• Emma Guilbaud
• Francesco M. Marincola

Programming immune escape

In a recent study published in Nature , Goto et al. explore mechanisms of immune evasion in early colorectal cancers and adenomas and identify SOX17 to be crucial for immune escape through suppression of interferon-γ signalling.

• Daniela Senft

NET-working under stress

In this recent study, He et al. establish that chronic stress promotes metastasis through stress-induced formation of neutrophil extracellular traps (NETs).

• Gabrielle Brewer

Biological age surges in survivors of childhood cancer

People who survived paediatric cancers age faster and are at higher risk of early death.

Functional precision medicine for pediatric cancers

A small, prospective clinical study shows that ex vivo drug screening of pediatric cancer samples can identify effective therapeutic options. If validated, these findings could herald a new approach to precision medicine in this setting.

• M. Emmy M. Dolman
• Paul G. Ekert

How to supercharge cancer-fighting cells: give them stem-cell skills

The bioengineered immune players called CAR T cells last longer and work better if pumped up with a large dose of a protein that makes them resemble stem cells.

The enduring neutrophil–stroma dance of multiple myeloma

Inflammatory memory cues initiated by neutrophils and bone marrow stroma suggest potential therapeutic targets for the treatment of multiple myeloma.

• Daniela Cerezo-Wallis
• Iván Ballesteros

Routes to second cancers

Sánchez-Guixé et al. investigated the possible routes to second malignancies in survivors of paediatric cancer by studying four such clinical cases.

Reporting outcome comparisons by sex in oncology clinical trials

Many aspects of human health and disease are influenced by sex as a biological variable and gender as a social construct. A recent study from Nature Communications reported the landscape of outcome comparisions by sex in oncology clinical trials, highlighting the need for a more thorough reporting of sex differences.

• Yuning Wang

Global post-mortem tissue donation programmes to accelerate cancer research

Metastatic cancer represents the main cause of death in patients with cancer, but metastasis research is hindered by the limited availability of metastatic samples. In this Comment, Desmedt and Carey highlight the opportunities and challenges of post-mortem tissue donation programmes, which represent a complementary and attractive solution to overcome many of the hurdles in metastasis research.

• Christine Desmedt
• Lisa A Carey

An immunological window to the brain

The eye and the brain are both recognized as immune-privileged sites. Research now indicates that responses in the eye mirror those in the central nervous system (CNS), offering major implications for the treatment of CNS cancers and infections.

• James T. Walsh
• Jonathan Kipnis

Pembrolizumab plus chemoradiotherapy effective in locally advanced cervical cancer

Neutrophil subsets.

• Ioana Staicu

The death gaze of MEDUSA

Chemogenetic profiling can reveal genetic determinants that coordinate phenotypic responses to therapeutics, along with predicting potential pathways of resistance. A new analytical method for evaluating chemogenetic profiles reveals contributions from death-regulatory genes.

• Jesse D. Gelles
• Jerry Edward Chipuk

Mirvetuximab soravtansine has activity in platinum-sensitive epithelial ovarian cancer

Methods & protocols.

Engineering megabase-sized genomic deletions with MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements)

The authors introduce MACHETE (molecular alteration of chromosomes with engineered tandem elements), a clustered regularly interspaced short palindromic repeats directed Cas9-based system for the efficient deletion of megabase-sized genomic regions.

• Francisco M. Barriga
• Scott W. Lowe

CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction

CONIPHER is a computational framework for accurately inferring subclonal structure and the phylogenetic tree from multisample tumor sequencing, accounting for both copy number alterations and mutation errors.

• Kristiana Grigoriadis
• Ariana Huebner
• Nicholas McGranahan

Robust scoring of selective drug responses for patient-tailored therapy selection

This protocol presents a computational approach to scoring drug sensitivity that integrates multiple dose–response parameters into a single response metric and identifies differences in drug-response patterns between cancer cells and healthy control cells.

• Yingjia Chen
• Tero Aittokallio

INVADEseq to identify cell-adherent or invasive bacteria and the associated host transcriptome at single-cell-level resolution

Invasion–adhesion-directed expression sequencing adapts the 10x Genomics 5′ single-cell RNA sequencing protocol to enable generation of bacterial and eukaryotic DNA libraries to identify adherent or invasive bacteria and the associated host transcriptome at a single-cell level.

• Jorge Luis Galeano Niño
• Susan Bullman

Genome-wide pooled CRISPR screening in neurospheres

The authors present a protocol for genome-wide clustered regularly interspaced short palindromic repeat screening of three-dimensional neurospheres.

• Amy B. Goodale
• David E. Root

Newly diagnosed AML: quizartinib improves OS

• David Killock

Promising results for antisense RNA therapy in mouse models of diffuse midline glioma

• Caroline Barranco

Serum tumour markers for testicular cancer recurrence

The current serum tumour markers α-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase show limited value for testicular cancer relapse detection. A recent study highlights that false-positive elevations in follow-up monitoring are common and, conversely, many patients do not have elevations despite proven relapse. These findings highlight the potential for circulating microRNAs to be used as improved biomarkers for relapse detection.

• Matthew J. Murray
• Cinzia G. Scarpini
• Nicholas Coleman

Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance

A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, T STR , was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.

CD4 + CAR T cells — more than helpers

Therapeutic products containing CD8 + and CD4 + T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4 + CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4 + T cells target tumors.

• M. Eric Kohler
• Terry J. Fry

Venetoclax–obinutuzumab combinations are effective in fit patients with CLL

Taking the temperature of lung cancer antigens

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

• Paul A. Stewart
• Alex M. Jaeger

A skull bone marrow niche for antitumour neutrophils in glioblastoma

A preprint by Lad et al. shows that tumour-associated neutrophils in glioblastoma originate from skull bone marrow and acquire an antigen-presenting cell phenotype intratumorally in the presence of local T cells.

• Austeja Baleviciute

Impaired RNA clearance

In this study, Insco et al. find patient-specific CDK13 mutations to impede RNA surveillance, leading to the accumulation and translation of prematurely terminated RNAs that drive malignancy in melanoma models.

Peptide-mediated CRISPR engineering of cells

An article in Nature Biomedical Engineering reports a simple and hardware-independent peptide-mediated delivery method for the CRISPR-mediated engineering of T cells.

• Nesma El-Sayed Ibrahim

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Our Discoveries

New research identifies a protein essential to maintaining chromosomal stability

Researchers discovered how overproduction of a protein called CENP-A can lead to chromosomal abnormalities, which are found in many types of cancer.

New database of sarcoma cell line data will drive rare cancer research

CCR researchers have developed the largest publicly accessible sarcoma cell line database called Sarcoma CellMinerCDB . The tool merges previously available and new sarcoma cell line data that can be used to identify new therapeutic targets for these cancers. 

Study sheds light on diversity of study participants at CCR

Diversity in clinical trials is critical for understanding how well a treatment may work in different populations. A new study describes representation based on sex, age and ethnicity in clinical trials done at CCR.

NIH researchers develop AI tool with potential to more precisely match cancer drugs to patients

In a proof-of-concept study published on April 18, 2024, in Nature Cancer , CCR researchers have developed an artificial intelligence (AI) tool that uses data from individual cells inside tumors to predict whether a person’s cancer will respond to a specific drug. The team, led by  Eytan Ruppin, M.D., Ph.D. , Chief of the  Cancer Data Science Laboratory , suggests that such single-cell RNA sequencing data could one day be used to help doctors more precisely match cancer patients with drugs that will be effective in treating their cancer.

Cellular processing reverses molecule’s effect on anticancer immunity

Immune cells convert an immunosuppressive lipid into an anticancer immunity enhancer.

New research on liver cell diversity could help scientists understand tumor complexity

Hepatocytes, the main cell type in the liver, differ in function according to their location in the liver. A new study shows that mitochondrial responses to nutrients drive this diversity — a finding that could help researchers better understand tumor cell heterogeneity.

New biomaterial enhances cancer vaccine effectiveness to help eliminate cancer in mice

Scientists have created a new type of cancer vaccine approach that uses a biomaterial that attracts immune cells and localizes the delivery of the vaccines. In mice, the biomaterial combined with a cancer vaccine was able to cure 50 to 75% of their tumors.

India’s First Homegrown CAR T-Cell Therapy Has Roots in NCI Collaboration

In October 2023, India’s counterpart to the US Food and Drug Administration, the Central Drugs Standard Control Organization, approved NexCAR19, an effective, low-cost CAR-T cell therapy. The development of the therapy was made possible by a years-long collaborative journey between the Indian Institute of Technology Bombay and Tata Memorial Centre in Mumbai with NCI researchers at the NIH Clinical Center. As India’s first approved CAR-T cell therapy, the treatment will be manufactured in Mumbai and is affordable for many. 

The liver controls intestinal health through the PEDF protein

A new study reveals how the liver and gut communicate to regulate stem cell expansion in the repair of damaged intestinal tissue. The finding, from the lab of Chuan Wu, M.D., Ph.D. , has important implications for a lipid-lowering drug that affects that communication.

PROTACtion against resistance of commonly used anti-cancer drug

Drugs known as PIM kinase inhibitors are used to treat a range of cancers, but many patients develop resistance to these medications. Recent research has led to a new class of therapeutics that target the mechanism of this resistance, resulting in increased death of cancer cells.

New findings about cancer cell growth may hold promise for future cancer treatments

For a cell to grow and divide, it needs to produce new proteins. This also applies to cancer cells. In a new study published today in Science Advances , researchers at Karolinska Institutet in Sweden have investigated the protein eIF4A3 and its role in the growth of cancer cells. The study shows that by blocking or reducing the production of this protein, other processes arise that cause the growth and cell division of cancer cells to cease and eventually die.

The body's normal cell division is carefully controlled, where genes in the cell regulate when it is time to start and stop cell division. Sometimes this balance is disturbed and the cell continues to divide uninhibitedly. After some time, a small collection of cells develops -- cancer may be about to form.

"When a cell grows, new proteins are produced, among other things, through the translation of the cell's DNA information into mRNA, which forms the basis for the creation of proteins. The cell also needs to manufacture rRNA for the cell's small factories, the ribosomes, which are responsible for producing proteins," says Associate Professor Mikael Lindström, co-author and part of Professor Jiri Bartek's research group at the Department of Medical Biochemistry and Biophysics who conducted the study.

In the study, the research group investigated cultured cancer cells and cancer tissue where the eIF4A3 protein's expression was high compared to normal tissue. By adding synthetically produced small molecules that can later be further developed into finished drugs, the production of eIF4A3 can be checked. The researchers then discovered two distinct changes in the cancer cells.

"Firstly, we saw that the blocking of eIF4A3 activated the protein p53, a protein that has an important role to play in fighting cancer cells," says Dimitris Kanellis, a postdoctoral fellow at the Department of Medical Biochemistry and Biophysics, and the first author of the study.

However, one challenge with many types of tumours is that the positive functions of the p53 protein are counteracted by another protein, MDM2.

"Interestingly, we noted that the blocking eIF4A3 also meant that the MDM2 protein changed. This change helps to maintain and strengthen p53 and can be beneficial when we want to inhibit the growth of cancer cells," continues Dimitris Kanellis.

The main conclusions of the study indicate that depletion or inhibition of eIF4A3 activates p53, alters the manufacturing process of proteins by disrupting ribosome biogenesis, and thereby inhibits the growth of cancer cells. Knowledge of the importance of the eIF4A3 protein opens up new opportunities for better and more effective treatment of cancer patients.

"The discovery is very relevant as this type of targeted treatment may represent a new possible approach in chemotherapy, for example in colon cancer where cancer cells often have a high level of ribosomes and rapid growth. Another example is a sarcoma, cancer of the body's support tissues, where we know that sometimes there is an overproduction of MDM2. This increases the chances of more effective treatment," says Associate Professor Mikael Lindström and Professor Jiri Bartek, corresponding authors in the study.

These findings provide an important foundation for further studies. However, since the study has mainly been carried out in cultured cancer cells and clinical tumour material, it remains to be seen how the blocking of eIF4A3 will affect the growth of cancer in vivo.

"There may also be synergies between the chemical compounds that block eIF4A3 and drugs that are already used to treat cancer that we will now research further," concludes Mikael Lindström.

The research was funded by the Swedish Research Council, the Cancer Foundation, the Swedish Childhood Cancer Foundation, ERC, and Karolinska Institutet.

• Lung Cancer
• Brain Tumor
• Colon Cancer
• Molecular Biology
• Cell Biology
• Biotechnology
• Chemotherapy
• Monoclonal antibody therapy
• Prostate cancer
• Adult stem cell

Story Source:

Materials provided by Karolinska Institutet . Note: Content may be edited for style and length.

Journal Reference :

• Dimitris C. Kanellis, Jaime A. Espinoza, Asimina Zisi, Elpidoforos Sakkas, Jirina Bartkova, Anna-Maria Katsori, Johan Boström, Lars Dyrskjøt, Helle Broholm, Mikael Altun, Simon J. Elsässer, Mikael S. Lindström, Jiri Bartek. The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output . Science Advances , 2021; 7 (32): eabf7561 DOI: 10.1126/sciadv.abf7561

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10 new breakthroughs in the fight against cancer

Medical advances are continuing to help the world fight cancer. Image:  Unsplash/National Cancer Institute

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This article was originally published in May 2022, and most recently updated in May 2024 .

• Cancer is one of the world’s biggest killers, with around 10 million deaths per year due to the disease.
• Scientists are using artificial intelligence, DNA sequencing, precision oncology and other technologies to improve treatment and diagnosis.
• The Centre for the Fourth Industrial Revolution India, a collaboration with the World Economic Forum, hopes to accelerate 18 cancer interventions.

Cancer kills around 10 million people a year and is a leading cause of death globally, according to the World Health Organization.

Breast, lung and colon cancer are among the most common. Death rates from cancer were falling before the pandemic . But COVID-19 caused a big backlog in diagnosis and treatment .

There is some good news, however. Medical advances are accelerating the battle against cancer. Here are 10 recent developments.

Test to identify 18 early-stage cancers

Researchers in the US have developed a test they say can identify 18 early-stage cancers. Instead of the usual invasive and costly methods, Novelna's test works by analyzing a patient's blood protein. In a screening of 440 people already diagnosed with cancer, the test correctly identified 93% of stage 1 cancers in men and 84% in women. The researchers believe the findings "pave the way for a cost-effective, highly accurate, multi-cancer screening test that can be implemented on a population-wide scale". It's early days, however. With such a small sample screening and a lack of information on co-existing conditions, the test is currently more of "a starting point for developing a new generation of screening tests for the early detection of cancer".

Seven-minute cancer treatment jab

England's National Health Service (NHS) is to be the first in the world to make use of a cancer treatment injection , which takes just seven minutes to administer, rather than the current time of up to an hour to have the same drug via intravenous infusion. This will not only speed up the treatment process for patients, but also free up time for medical professionals. The drug, Atezolizumab or Tecentriq, treats cancers including lung and breast, and it's expected most of the 3,600 NHS patients in England currently receiving it intravenously will now switch to the jab.

Precision oncology

Precision oncology is the “ best new weapon to defeat cancer ”, the chief executive of Genetron Health, Sizhen Wang, says in a blog for the World Economic Forum. This involves studying the genetic makeup and molecular characteristics of cancer tumours in individual patients. The precision oncology approach identifies changes in cells that might be causing the cancer to grow and spread. Personalized treatments can then be developed. The 100,000 Genomes Project, a National Health Service initiative, studied more than 13,000 tumour samples from UK cancer patients , successfully integrating genomic data to more accurately pin-point effective treatment. Because precision oncology treatments are targeted – as opposed to general treatments like chemotherapy – it can mean less harm to healthy cells and fewer side effects as a result.

Artificial intelligence fights cancer

In India, World Economic Forum partners are using emerging technologies like artificial intelligence (AI) and machine learning to transform cancer care. For example, AI-based risk profiling can help screen for common cancers like breast cancer, leading to early diagnosis. AI technology can also be used to analyze X-rays to identify cancers in places where imaging experts might not be available. These are two of 18 cancer interventions that The Centre for the Fourth Industrial Revolution India, a collaboration with the Forum , hopes to accelerate.

Greater prediction capabilities

Lung cancer kills more people in the US yearly than the next three deadliest cancers combined. It's notoriously hard to detect the early stages of the disease with X-rays and scans alone. However, MIT scientists have developed an AI learning model to predict a person's likelihood of developing lung cancer up to six years in advance via a low-dose CT scan. Trained using complex imaging data, 'Sybil' can forecast both short- and long-term lung cancer risk, according to a recent study. "We found that while we as humans couldn't quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer," said co-author Jeremy Wohlwend.

Clues in the DNA of cancer

At Cambridge University Hospitals in England, the DNA of cancer tumours from 12,000 patients is revealing new clues about the causes of cancer, scientists say. By analyzing genomic data, oncologists are identifying different mutations that have contributed to each person’s cancer. For example, exposure to smoking or UV light, or internal malfunctions in cells. These are like “fingerprints in a crime scene”, the scientists say – and more of them are being found. “We uncovered 58 new mutational signatures and broadened our knowledge of cancer,” says study author Dr Andrea Degasperi, from Cambridge’s Department of Oncology.

Liquid and synthetic biopsies

Biopsies are the main way doctors diagnose cancer – but the process is invasive and involves removing a section of tissue from the body, sometimes surgically, so it can be examined in a laboratory. Liquid biopsies are an easier and less invasive solution where blood samples can be tested for signs of cancer. Synthetic biopsies are another innovation that can force cancer cells to reveal themselves during the earliest stages of the disease.

The application of “precision medicine” to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseases—and disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forum’s Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access – across borders – to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a “federated data system”: a decentralized approach that allows different institutions to access each other’s data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

CAR-T-cell therapy

A treatment that makes immune cells hunt down and kill cancer cells was declared a success for leukaemia patients in 2022. Known as CAR-T-cell therapy, it involves removing and genetically altering immune cells, called T cells, from cancer patients. The altered cells then produce proteins called chimeric antigen receptors (CARs), which can recognize and destroy cancer cells. In the journal Nature , scientists at the University of Pennsylvania announced that two of the first people treated with CAR-T-cell therapy were still in remission 12 years on.

However, the US Food and Drug Administration is currently investigating whether the process can in fact cause cancer , after 33 cases of secondary cancer were observed in patients receiving CAR-T therapies. The jury is still out as to whether the therapy is to blame but, as a precaution, the drug packaging now carries a warning.

Fighting pancreatic cancer

Pancreatic cancer is one of the deadliest cancers. It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years. At the University of California San Diego School of Medicine, scientists developed a test that identified 95% of early pancreatic cancers in a study. The research, published in Nature Communications Medicine , explains how biomarkers in extracellular vesicles – particles that regulate communication between cells – were used to detect pancreatic, ovarian and bladder cancer at stages I and II.

Have you read?

Cancer: how to stop the next global health crisis, how to improve access to cancer medicines in low and middle-income countries, why is cancer becoming more common among millennials, a tablet to cut breast cancer risk.

A drug that could halve the chance of women developing breast cancer is being tested out by England's National Health Service (NHS). It will be made available to almost 300,000 women seen as being at most risk of developing breast cancer, which is the most common type of cancer in the UK . The drug, named anastrozole, cuts the level of oestrogen women produce by blocking the enzyme aromatase . It has already been used for many years as a breast cancer treatment but has now been repurposed as a preventive medicine. “This is the first drug to be repurposed through a world-leading new programme to help us realize the full potential of existing medicines in new uses to save and improve more lives on the NHS," says NHS Chief Executive Amanda Pritchard.

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Our top 5 cancer research breakthroughs of 2022

15th December 2022

2022 has likely been your first full year back to ‘normal’ since the COVID-19 pandemic, and that’s no different for cancer researchers. Back into full swing in the lab, Worldwide Cancer Research scientists have been busy making exciting new discoveries about cancer. Here are the top five cancer research breakthroughs made by our scientists in 2022.

1. Stopping the spread of breast cancer

Our scientists in Italy discovered a previously unknown way that breast cancer cells survive treatment . They found that breast cancer cells hiding in places like the lungs seem to rely on specific antioxidants to survive there. This could be a new way to wipe out breast cancer cells that have escaped treatment.

Click here to read more about this incredible discovery, or find out what other ground-breaking work we're funding .

Our hope is that these findings can be translated into a real drug treatment that can kill “sleeping” cancer cells before they awake into full-blown metastases.

2. Stool samples can reveal pancreatic cancer sooner

Our researchers in Spain, led by Dr Núria Malats, have found a new way to spot if someone is at higher risk of pancreatic cancer, and even diagnose patients at an early stage of the disease . Specific microorganisms in a stool sample could signal that there is a problem in a rapid, non-invasive, and affordable way.

Read the full story here , or find out what else our scientists have discovered about pancreatic cancer this year.

This new breakthrough builds on the growing evidence that the microbiome is linked to the development of cancer. Early detection and diagnosis are just as important an approach to starting new cancer cures as developing treatments.

Become a Curestarter today and join us in supporting pioneering cancer research breakthroughs like these in 2023.

3. targeting cancer’s energy supply.

Our scientists in Germany discovered they could prevent head and neck cancer spreading by stopping it getting the extra energy it needs to do so. If they prevented a change happening in the RNA of mitochondria (the powerhouse of the cell), the cancer didn’t spread as much.

Click here to learn more about this breakthrough, or learn how your donations are used to start cancer cures .

The funding from Worldwide Cancer Research helped us to get a step closer to succeeding in fighting cancer metastasis, the leading cause of cancer death.

4. Making radiotherapy work for more patients

Our researchers in Spain made a breakthrough that could help treat people with cancer that has spread to the brain . In the future, a blood test could reveal if patients will respond to radiotherapy or if the cancer will resist it, then a drug called a RAGE inhibitor could make radiotherapy work better for those that would resist it.

Learn more about this important discovery , or read Anne and Cathrin's personal story.

We are very excited about the findings of this study and specifically the drug we have found. We really hope that what we have discovered will lead to a new way to personalise the use of radiotherapy that maximises the benefits for each patient.

5. Engineering immune cells to hunt down cancer

Our researchers in Italy have made a breakthrough that could lead to better, more effective immunotherapy options for cancer patients . They discovered how to engineer a specific type of immune cell to target and kill cancer cells, then boost its cancer-killing ability using a drug delivered with nanotechnology.

Find out the full story , or see how we've contributed to the discovery of new immunotherapies .

We hope we have laid the foundations for an innovative approach of adoptive cell therapy of cancer, hopefully more efficient than the current ones.

Breakthroughs of the future: 2023!

And finally, we were delighted to commit to funding £5.3 million to 25 new research projects that will start in 2023! It is incredibly important to continue supporting ground-breaking discovery cancer research if we hope to end the suffering caused by cancer.

Breakthroughs like these are vital if we hope to end the suffering caused by cancer. Unfortunately, funding for discovery research has dropped by ~25% in recent years.

Become a Curestarter today and you can help start new cancer cures.

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Recent developments in cancer research: Expectations for a new remedy

1 Department of Surgery and Science, Kyushu University, Fukuoka Japan

Qingjiang Hu

Yuta kasagi, masaki mori.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Cancer research has made remarkable progress and new discoveries are beginning to be made. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiomes, immunotherapy, and organoids.

1. INTRODUCTION

The cancer research field has developed significantly through use of new equipment and technology. One example of new technology is Next‐Generation Sequencing (NGS). Also known as high‐throughput sequencing, NGS is the catch‐all term used to describe a number of different modern nucleic acid sequencing technologies. These methods allow for much quicker and cheaper sequencing of DNA and RNA compared with the previously used Sanger sequencing, and as such have revolutionized the study of genomics and molecular biology. NGS also allows for easier detection of mutations in cancer samples, leading to development of many new agents that can be used to treat patients. For example, if the RAS gene status is detected as wild type in a colorectal cancer patient, then an anti‐EGFR antibody, such as cetuximab or panitumumab, can be used for treatment.

A liquid biopsy, also known as fluid biopsy or fluid phase biopsy, is the sampling and analysis of non‐solid biological tissue, primarily blood. 1 It is being used as a novel way to detect cancer. Like a traditional biopsy, this type of technique is mainly used as a diagnostic and monitoring tool for diseases, and also has the added benefit of being largely noninvasive. Therefore, liquid biopsies can be performed more frequently, allowing for better tracking of tumors and mutations over a duration of time. This technique may also be used to validate the effectiveness of a cancer treatment drug by taking multiple liquid biopsy samples in the span of a few weeks. It may also prove to be beneficial for monitoring relapse in patients after treatment.

Novel devices and drugs have also been developed and used for cancer treatment. For surgery procedures, robotic‐assisted laparoscopic surgery has evolved and made it possible to visualize the fine movement of the forceps in three dimensions. This method is now used in esophageal, gastric, and rectal cancer surgeries in Japan. 2 , 3 , 4

Recently, immunotherapy became an additional method for treating cancer patients. The discovery of the immune checkpoint by Dr Honjo led to the development of immune checkpoint inhibitors. 5 Despite these developments, gastrointestinal cancers are still a major problem in need of new treatment methods. In this review, we introduce and describe four new areas of cancer research that may contribute to cancer treatment in the future: exosomes, microbiome, immunotherapy, and organoids.

2. AN APPLICATION OF EXOSOME RESEARCH IN CANCER THERAPY

An exosome is a small particle that is secreted by cells. Its size can range from 50 to 150 nm and has a surface consisting of proteins and lipids that originate from the cell membrane. Additionally, proteins and nucleic acids, such as DNA, microRNAs, and mRNAs, can be found inside the exosome as its “cargo.” 6 Recently, many researchers have discovered that exosomes are involved in the mechanisms of various diseases. As mentioned above, various functional compounds, such as microRNAs, mRNAs, and proteins, can be contained within exosomes. 7 , 8 Many cells use secretion of exosomes to communicate with one another, and these exosomes can even reach distant cells. Cancer cells can also secrete exosomes that contain molecules beneficial to cancer growth. For example, microRNAs found in cancer exosomes can modulate gene expression to induce angiogenesis in the tumor microenvironment, which supports metastasis. 9 Exosomes released from cancer cells can also reportedly break the blood‐brain barrier, which makes it contribute to brain metastasis. 10 , 11 Cancer cells themselves are similarly affected by the exosomes secreted by the surrounding normal cells. 12 In one case, the exosomes secreted by bone marrow‐delivered mesenchymal stem cells can force cancer cells into a dormant state. 13 These dormant cancer cells become resistant to chemotherapy and are involved in long‐term disease recurrence. Thus, exosomes are deeply involved in cancer proliferation, invasion, and metastasis, as well as in the formation of the tumor microenvironment and pre‐metastatic niche. 13 Further research on cancer‐related exosomes is ongoing.

Knowledge of exosomes can be applied to cancer treatment. If the secretion of exosomes from cancer cells can be prevented, then signal transduction supporting the formation of the tumor microenvironment and pre‐metastatic niche can be blocked. Work focusing on the removal of cancer exosomes is now ongoing. 14

Exosomes can also be utilized for cancer diagnosis. Exosomes secreted by many cell types are found in various body fluids, such as blood and urine. Capturing and analyzing exosomes from cancer cells can be used to detect the presence of disease. 15 Obtaining blood or urine from patients is not very invasive or painful. Since many molecules, such as various proteins, DNA, and microRNAs, can be found in exosomes from normal cells, it is important to distinguish them from cancer‐related ones. If exosomes are to be used for cancer diagnosis, then specific biomarkers need to be discovered. Additionally, the development of a method to detect these exosomes must be done. Currently, exosome detection methods for exosomes abundantly found in the serum of colorectal and pancreatic cancer patients, as well as exosomes found in the urine of bladder cancer patients, are being developed. 16 , 17 Thus, further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods, is significantly affected by exosome research.

3. MICROBIOME IN CANCER RESEARCH

A large number of microorganisms inhabit the human body. These microorganisms include bacteria, viruses, and fungi. Among them, bacteria have the most important relationship with the human body. Bacteria can live anywhere within the human body, including the digestive tract, respiratory system, and oral cavity. 18 , 19 , 20 In particular, bacteria in the digestive tract are rich in type and number, 21 with possibly 1000 types and more than 100 trillion individual bacterial cells present. 22 , 23 The overall population of various bacteria found in the human intestine is referred to as the “intestinal flora.” Recently, the terms “microbiota” or “microbiome” have also been widely used.

Recent advancements with NGS have led to a much more precise understanding of the intestinal microbiome. 24 The bacteria in the human microbiome mainly belong to four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteri. Of these, Firmicutes and Bacteroidetes are the most dominant species. It is reported that microbiome vary depending on age and race. 25 , 26 Dysbiosis is a condition in which the diversity of the microbiome is reduced. Dysbiosis is reportedly involved in various diseases such as inflammatory bowel disease, colorectal cancer, obesity, diabetes, and allergic diseases. 27 , 28 , 29 For example, bacteria such as Atopobium parvulum and Actinomyces odontolyticus increase in number during the early stages of colorectal cancer (adenomas or intramucosal cancers) and decrease in number during cancer progression. 30 This suggests that a specific microbiome is associated with early stages of colorectal cancer development, which may be useful knowledge for early cancer detection.

Various studies have also been conducted to elucidate the relationship between the microbiome and the human immune system. 31 The IgA antibody, which is one of the most important elements in the intestinal immune system, is believed to play a role in the elimination of pathogens and maintenance of the intestinal environment. The IgA antibody recognizes, eliminates, and neutralizes pathogenic bacteria and toxins. It also maintains a symbiotic relationship by recognizing and binding to the normal microbiome of the host. 32 Mice lacking a microbiome have reduced production of the IgA antibody. A microbiome is required for IgA antibody differentiation. Recent studies have identified W27IgA antibodies that have the ability to bind to various bacteria. 33 Oral administration of a W27IgA antibody to enteritis model mice suppressed enteritis by altering the microbiome. This W27IgA antibody can recognize a part of the amino acid sequence of serine hydroxymethyl transferase, which is a metabolic enzyme involved in bacterial growth. The W27IgA antibody can suppress the growth of E coli by binding to them. However, the W27IgA antibody does not bind to bacteria that suppress enteritis, such as bifidobacteria and lactic acid bacteria. 33 Thus, the microbiome is deeply involved in human intestinal immunity. Recently, it is having been established that the microbiome is not only involved in intestinal immunity, but also in the systemic immune system.

As the analysis of the microbiome progresses, the pathophysiology of various diseases, such as cancers, and its relationship with the regulatory function of the human immune system will be further elucidated. It has been demonstrated that F nucleatum plays a role in the development and progression of colon adenomas and colorectal cancer. It is also related to lymph node metastases and distant metastasis. 34 , 35 Also, microbiome is associated with hepatocellular carcinoma. 36 Studying microbiome will give us some clue in the development and remedy for gastrointestinal cancers (Table  1 ).

Gastrointestinal cancer and their related microbiome

4. THE RISE OF IMMUNOTHERAPY IN CANCER TREATMENT

For many years, surgery, chemotherapy, and radiation therapy were the main methods of cancer treatment. In addition to these therapies, immunotherapy has recently attracted great attention worldwide (Table  2 ). 37 , 38 Under normal circumstances, a cancer antigen will activate the patient's immune system to attack the cancer cells. However, sometimes the immune system does not recognize the cancer cells as non‐self, or it simply fails to attack them. This can result in the development and progression of cancer.

Immune checkpoint inhibitors

Although therapies that activate the immune system against cancer cells have been studied for a long time, the use of the patient's own immune system for cancer treatment was not established. Recently, the effectiveness of both immune checkpoint inhibition therapy and chimeric antigen receptor (CAR)‐T cell therapy has proved to be promising. 39 , 40 Immunotherapy has moved to the forefront of cancer treatment strategies.

There are two major reasons why proving the efficacy of cancer immunotherapies was difficult for some time. First, cancer immunity is strongly suppressed. Signal transduction from immune checkpoint compounds, such as PD‐1 and CTLA4, strongly inhibits cytotoxic T cells (CTLs). 38 This checkpoint mechanism can prevent the immune system from attacking cancer cells. The development of immune checkpoint inhibitors has arisen from the discovery of this mechanism. Inhibition of immune checkpoint molecules with neutralizing antibodies can release the suppression of cancer‐specific CTLs, activate immunity, and promote cancer elimination. The effectiveness of immune checkpoint antibodies has been confirmed and clinically applied to many solid cancers such as melanoma, 41 lung cancer, 42 urothelial cancer, 43 gastric cancer, 44 and esophageal cancer. 45 In addition to PD‐1 and CTLA4, new immune checkpoint molecules, such as LAG3, TIGIT, and SIRPA, are also being actively studied. 46 , 47 , 48 Although this therapy is promising, the cancer cases who respond to these therapies are limited. This is because use of this therapy requires the presence of cancer‐specific CTLs in the patient's body. To maximize the therapeutic effect, it is desirable to select appropriate cases and develop useful biomarkers.

The second difficulty for immunotherapy is that T cells do not recognize specific cancer cell antigens and immune accelerators are too weak. One goal of CAR‐T cell therapy is to strengthen the immune accelerator by administering CTLs to the patient's body that recognize specific cancer cell‐specific antigens. A CAR is prepared by fusing a single chain Fv (scFv), derived from a monoclonal antibody that recognizes a specific antigen expressed by cancer cells, with CD3z and costimulatory molecules (CD28, 4‐1BB, and others). Next, the CAR is introduced to the T cells obtained from a cancer patient and CAR‐T cells are made. CAR‐T cells recognize the specific antigen of the cancer cells and are activated to damage these cells. CAR‐T cells recognize cancer‐specific antigens with high antibody specificity and attack the respective cancer cells with strong cytotoxic activity and high proliferative activity. CAR‐T therapy is effective in blood cancers such as B‐cell acute lymphoblastic leukemia and myeloma. 49 , 50 While CAR‐T cell therapy has a high therapeutic effect, a frequent and serious adverse event called cytokine release syndrome has been observed in some patients. 51 , 52 The development of a technique for suppressing the occurrence of cytokine release syndrome is anticipated. In addition, the development of CAR‐T cell therapies for solid tumors is ongoing.

Recently, there was new progress made in treating gastrointestinal cancer patients. For MSI‐H colorectal cancer, the combination therapy with nivolumab and ipilimumab was approved. From the nivolumab plus ipilimumab cohort of CheckMate‐142, progression‐free survival rates were 76% (9 months) and 71% (12 months); respective overall survival rates were 87% and 85% which were quite high. This new treatment will benefit MSI‐H colorectal cancer patients. 53

Thus, it is expected that further understanding of cancer immune mechanisms and the development of various immunotherapies will contribute to great progress in cancer treatment.

One problem for immunotherapy is that there is no certain predictive biomarker. It was thought that the expression of PD‐1 or PD‐L1 would predict the effect. However, this was not the case. To find a new biomarker, we assessed the cytolytic activity (CYT) score. The CYT score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We are now evaluating CYT score in gastric cancer patients (data not published). The development in the biomarker search will benefit many gastrointestinal cancer patients.

5. ADVANTAGES FOR USING ORGANOIDS IN CANCER RESEARCH

The three‐dimensional (3D) organoid system is a cell culture‐based, novel, and physiologically relevant biologic platform. 54 An organoid is a miniaturized and simplified version of an organ that is produced in vitro in 3D and shows realistic microanatomy. With only one to a few cells isolated from tissue or cultured cells as the starting material, organoids are grown and passaged in a basement membrane matrix, which contributes to their self‐renewal and differentiation capacities. 54 , 55 The technique used for growing organoids has rapidly improved since the early 2010s with the advent of the field of stem cell biology. The characteristics of stem, embryonic stem cells (ES cells), or induced pluripotent stem cells (iPS cells) that allow them to form an organoid in vitro are also found in multiple types of carcinoma tissues and cells. Therefore, cancer researchers have applied ES cells or iPS cells in their field. 56 , 57 , 58

Organoid formation generally requires culturing stem cells or their progenitor cells in 3D. 54 , 55 The morphological and functional characteristics of various types of carcinoma tissue have been recapitulated in organoids that were generated from single‐cell suspensions or cell aggregates. These suspensions or aggregates were isolated from murine and human tissues or cultured cells, as well as from cancer stem cells propagated in culture. The structures of the organoids show the potential of cancer stem cell self‐renewal, proliferation, and differentiation abilities, and also provide insights into the roles of molecular pathways and niche factors that are essential in cancer tissues. 56 , 57 , 59 , 60 , 61 , 62 The organoid system also has been utilized for studying multiple biological processes, including motility, stress response, cell‐cell communications, and cellular interactions that involve a variety of cell types such as fibroblasts, endothelial cells, and inflammatory cells. These interactions are mediated via cell surface molecules, extracellular matrix proteins, and receptors in the microenvironment under homeostatic and pathologic conditions.

Although the organoid system is a complex and not effortless procedure that requires specific media, supplements, and many tricky techniques, 58 , 63 application of this system has been extended to a variety of cell types from different carcinomas (colorectal, pancreatic, prostate, breast, ovary, and esophageal cancers). 56 , 57 , 59 , 60 , 61 An organoid is generally induced within a few days to weeks, and is faster and less costly than the murine xenograft assay. Furthermore, applying novel genetic manipulations (e.g. CRISPR‐Cas9) can be carried out in the organoid system. 64 , 65

Kasagi et al modified keratinocyte serum‐free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of esophageal cancers. 64

We anticipate that many experimental results that utilize the organoid system will be published in the future.

The 3D organoid system has emerged in the past several years as a robust tool in basic research with the potential to be used for personalized medicine. 66 By passaging dissociated primary structures to generate secondary 3D organoids, this system can be performed using live tissue pieces obtained from biopsies, operative‐resected specimens, or even frozen tissues. This method has the potential to transform personalized therapy. For example, in the case of cancer recurrence, an effective chemotherapy can be selected by testing the chemotherapeutic sensitivity of cancer‐derived organoids from an individual patient's tissue stocks. In many cases, a patient's organoid accumulation is helpful for testing the sensitivity of novel therapeutic agents for treating carcinoma. 66 Hence, it appears that organoid biology will further develop with a goal of translating the research into personalized therapy.

6. SUMMARY AND FUTURE DIRECTIONS

This review describes four new cancer‐related studies: exosomes, microbiome, immunotherapy, and organoids (Figure  1 ).

The summary of the four cancer research areas. In this figure the summary of the four cancer research areas is shown: exosome, microbiome, immunotherapy, and organoid research

Since exosomes are released in blood or urine, if the capturing system is established, it will be a less invasive test to diagnose cancer. In the present, the presence of circulating tumor DNA (ctDNA) is one of the tools to detect the minimal residual disease. However, since ctDNA is only DNA, it is difficult to spread to cancer research. In that respect, as exosomes include not only DNA but also other nucleic acids and proteins, this will be a new tool for cancer research such as the diagnosis of early cancer.

Microbiome may lead to improved cancer diagnosis and treatment. Detecting a specific microbiome in a gastrointestinal tract may predict a specific cancer. And changing microbiome in some way may result in preventing cancer development.

Organoids may help address the problem of drug resistance, and also lead to the development of personalized therapy. However, producing organoids takes time and testing the drug resistance may take more time. If we could overcome these problems, the research into organoids can contribute to overcoming cancer.

As shown in Table  3 , many new studies and findings are reported into this field of research. These four novel cancer research areas will make many contributions to the diagnosis and treatment of cancer.

Recent studies on exosome, microbiome, immunotherapy, and organoids

Conflict of Interest: All the authors have no conflict of interest to disclose.

ACKNOWLEDGMENTS

We thank Dr Hirofumi Hasuda and Dr Naomichi Koga for their help in preparing this manuscript. We also thank J. Iacona, PhD, from Edanz Group for editing a draft of this manuscript.

Ando K, Hu Q, Kasagi Y, Oki E, Mori M. Recent developments in cancer research: Expectations for a new remedy . Ann Gastroenterol Surg . 2021; 5 :419–426. 10.1002/ags3.12440 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

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National Cancer Research Month: 7 CU Boulder discoveries that could improve, save lives

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From developing new therapies to help patients cope with anxiety to discovering new ways to treat resistant breast cancer and new environmentally friendly methods for producing chemotherapy drugs, CU Boulder researchers are pushing boundaries in cancer research. In recognition of National Cancer Research Month, here’s a sampling of recent projects.

Geologists, biologists unearth the atomic fingerprints of cancer

Earth scientists have long turned to minute differences in hydrogen atoms to explore the ancient history of our planet. A new study suggests that these same tiny atoms could one day lead to new ways to track the growth of cancer.

Writing to wellness: New therapy helps cancer patients face biggest fears

With new medications extending the lives of advanced cancer patients, many live for years in the face of radical uncertainty. A new CU Boulder-born therapy has been shown to reduce trauma, depression, anxiety and fear.

How silencing a gene-silencer could lead to new cancer drugs

CU Boulder research reveals how a molecular machine known as PRC2 helps determine which cells become heart cells, versus brain or muscle or skin cells. The findings shed light on how development occurs and could pave the way for novel cancer treatments.

Why breast cancer survivors don’t take their meds, and what can be done about it

Hormone-blocking drugs can be life-saving for breast cancer survivors, reducing risk of recurrence by as much as 50%. Yet many patients stop taking them early or don’t take them as directed. CU Boulder research explores why, and what can be done about it.

When it comes to treating resistant breast cancer, 2 drugs may be better than 1

CU Boulder research shows that cancer cells can adapt in as little as one to two hours to new drugs called CDK2 inhibitors. The good news: Adding a second, widely available drug disables this workaround, squelching tumor growth.

New ‘magic beans’ produce ingredients for cancer treatments, vaccines, more

Tens of thousands of sharks are killed each year to harvest a key ingredient for vaccines, while old growth trees are slashed to obtain chemotherapy ingredients. Soybean farmer-turned molecular biologist Brian DeDecker has a better idea.

Researchers identify promising new target for drug-resistant breast and ovarian cancers

By inhibiting a protein that helps cancer cells repair themselves, scientists hope to develop new drugs that treat resistant tumors with fewer side effects.

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Perspective article, the biophysics of water in cell biology: perspectives on a keystone for both marine sciences and cancer research.

• Inserm, CNRS, CRCI 2 NA, Nantes Université, University of Angers, Angers, France

The biophysics of water, has been debated over more than a century. Although its importance is still underestimated, significant breakthroughs occurred in recent years. The influence of protein condensation on water availability control was documented, new findings on water-transport proteins emerged, and the way water molecules rearrange to minimize free energy at interfaces was deciphered, influencing membrane thermodynamics. The state of knowledge continued to progress in the field of deep-sea marine biology, highlighting unknown effects of high hydrostatic pressure and/or temperature on interactions between proteins and ligands in extreme environments, and membrane structure adaptations. The role of osmolytes in protein stability control under stress is also discussed here in relation to fish egg hydration/buoyancy. The complexity of water movements within the cell is updated, all these findings leading to a better view of their impact on many cellular processes. The way water flow and osmotic gradients generated by ion transport work together to produce the driving force behind cell migration is also relevant to both marine biology and cancer research. Additional common points concern water dynamic changes during the neoplastic transformation of cells and tissues, or embryo development. This could improve imaging techniques, early cancer diagnosis, and understanding of the molecular and physiological basis of buoyancy for many marine species.

1 Introduction

Water is essential to the biosphere, shaping the earth and making life possible, where alteration of oceanic crust and serpentinization process play fundamental roles ( Brovarone et al., 2020 ; Andreani et al., 2023 ; Schwander et al., 2023 ). In addition to being the medium of biology, water also represents the main actor in metabolism ( Frenkel-Pinter et al., 2021 ). The biophysics of water, a central question for both marine biology and biomedical sciences, is a potential transdisciplinarybridge, and after more than a century of investigations, it is still receiving increasing attention, raising questions and perspectives. The anomalous properties of liquid water, continuously debated with, are still challenged ( Urbic and Dill, 2018 ). In cell biology, the importance of water has always been underestimated, however its role in protein folding and structure, proton and electron transfer, nucleic structure, and communication at a distance were emphasized ( Chaplin, 2006 ). Given all the breakthroughs published in the literature, it is crucial that we consider the concept of ‘water as a biomolecule’ ( Ball, 2008 ) to avoid missing an essential part of knowledge for students and researchers in the future. Instead, the cytomatrix should be viewed as a cooperative system of supramolecular water-ion-protein complexes ( Shepherd, 2006 ).

A major point in understanding water’s biophysical properties in the intracellular environment is its evolution in a very crowded space ( Fayer, 2011 ). Reviewing its role in the subcellular structuring of a prokaryotic cell, Spitzer looked back to the pioneering studies conducted on marine species, and suggested viewing the physical and chemical interactions and processes that structure the cytoplasm through a ‘complex vectorial (bio)chemistry’ ( Spitzer, 2011 ). Another consequence is that water entropy is maximized, with an impact on the cytoskeleton and gene expression ( Li et al., 2022 ). Evidence that crowding provided a mechanism by which cells are sensitive to their volume change had previously been supported by experimental observations ( Burg, 2000 ), a significant parameter for egg and embryo buoyancy in marine species, and thus their ecological behavior. Meanwhile, direct observation of the spatial distribution of water molecules inside a living cell has revealed different crowding environments in the nucleus and cytoplasm ( Takeuchi et al., 2017 ).

Active fluxes of water and solutes of water play an essential role during cell shape changes and cell motility, emphasizing the role of hydraulic pressure in cell dynamics ( Li et al., 2020 ). Cell volume regulation also involves ion/water transport systems, and the last two decades were characterized by tremendous insight into the role of aquaporins ( Verkman, 2005 ; Papadopoulos et al., 2008 ). Besides the cytoskeleton, which had long been suggested as generating the driving force for cell migration, the water flow due to osmotic gradients generated by localized ion transport across the plasma membrane also contributes to this process ( Morichita et al., 2019 ). Experimental evidence for anomalous diffusion of water in biological tissues, measured by nuclear magnetic resonance (NMR) has been extensively documented ( Köpf et al., 1996 ), leading to the development of diffusion-weighted magnetic resonance imaging (DW-MRI), applied to cancer diagnosis and follow-up after treatment ( Patterson et al., 2008 ). Interestingly, the role played by another technique, quasielastic neutron scattering (QENS), provided additional value in understanding the role played by water molecules in tumors before and after treatment with chemotherapy drugs ( Martins et al., 2022 ).

As an echo to biophysical investigations on structured (bound) water in cell biology ( Pouliquen et al., 2006a ; 2006b ), a long-distance effect for structured water was observed, related to an ordering of water molecules binding to specific sites on surfaces such as biological membranes, forming localized clusters corresponding to what is called today an ‘exclusion zone’ ( Chen et al., 2012 ). This term of ‘structured water’, commonly used by numerous NMR investigators of water in biological systems from the 1970s to the 1990s, refers to the gel-like consistency of water in the intracellular environment, nicely described by Pollack, who argued for a ‘marriage between interface science and biology’ ( Pollack, 2003 ). In this vision, one last crucial parameter of the problem is also represented by the strength of hydration, which is charge density-dependent ( Collins, 1997 ). Meanwhile, improvements were made in the knowledge of the ‘water affinity’ of the different ions, another interesting question of interest common to both marine and biomedical sciences ( Collins, 2019 ).

Investigations on water properties in membrane interfaces ( Disalvo et al., 2008 ) have progressively led to seeing water as a structural and thermodynamic component of biomembranes ( Disalvo et al., 2022 ). Given the impact of the crowding effect on the thermodynamics of metabolic reactions, the way water shapes proteins was recently documented, revealing its role in protein stabilization ( Crilly et al., 2021 ). In parallel, water wires were shown to be critical for the functioning of membrane proteins ( Paulino et al., 2020 ). Protein stabilization is also a key issue for preserving living cells and tissues. As different freezing approaches are currently used, the molecular interplay between cryoprotectants and water/ice were analyzed using molecular dynamics simulations in the context of protein stabilization and preservation of cell membranes ( Weng et al., 2019 ). Water being replaced by sugars, the way in which extremotolerant organisms exploit sugars as desiccation protectants for preserving protein structure is another area undergoing intense investigations ( Brom et al., 2023 ). Finally, biophysical studies of organisms living in extreme conditions revealed mechanisms for sensing water stress and the relevant signal transduction pathways involved in cellular responses to water-deficit stress ( Caramelo and Iusem, 2009 ).

Here, starting with a survey of the most recent findings, we will examine questions relevant to both marine biology and cancer research ( Figure 1 ), pointing to some potential intellectual bridges between them, likely to open interesting prospects for the future.

Figure 1 . An illustration of the different topics corresponding to potential intellectual bridges at the interface between the biophysics of water in the cell/marine biology/cancer research. Subtopics relevant to water biophysics are illustrated in blue rectangles (uppercase letters). Thicker arrows represent suggestions for priority research fields likely to open innovative perspectives. Some connections between terms (symbolized by arrows) were voluntarily removed for clarity.

2 Recent breakthroughs on the biophysics of water in the cell

The mechanisms of water movements have received considerable attention. The role played by aquaporins in regulating migration-related processes was reviewed, highlighting their complex interrelationships with cell volume change, and signaling pathway activation ( Smith and Stroka, 2023 ). Based on simulations of cellular water exchange, improved current physical diffusion models were proposed ( Gardier et al., 2023 ). This is in line with parallel findings revealing vascular leakiness to circulating fluids, involving endothelial cell gap formation related to lamellipodia dynamics ( Arce et al., 2023 ). The question of membrane water permeability was also updated through changes in membrane structure. For example, calcitriol, a unique component of the Helicobacter pylori membrane, facilitates water transport, crossing from one layer to another more easily than cholesterol ( Cao et al., 2024 ).

Salinity or membrane composition also tune the interactions between biomolecular condensates and membranes, a reciprocal mechanism existing between water activity and supramolecular rearrangement, with protein secondary structure altering water dynamics in turn ( Mangiarotti et al., 2023 ). The way biomolecular condensation of intrinsically disordered proteins controls water availability in cells was also investigated ( De Souza and Stone, 2023 ; Watson et al., 2023 ). Additional findings improving our understanding of cellular condensates were the dissection of the role played by water-mediated interactions in a prototypical cellular condensate environment using long-timescale atomistic simulations ( Brown and Potoyan, 2024 ). The difficulty with studying water structure within cells directly was overcome by demonstrating the power of the water bend-libration combination band using Raman spectral imaging. This revealed fascinating images of cellular water subpopulations within neuroblastoma cells ( Ramos and Lee, 2023 ). The consequence of the crowded space on water activity was also studied in the mitochondrial matrix, revealing the impact of its changes on biochemical reactions ( Bulthuis et al., 2023 ). Another case showed the impact of crowding and cellular interactions on in vivo folding of the three-helix bundle protein B in the cytoplasm ( Russell et al., 2023 ). Finally, the way macromolecular crowding affected the enzymatic reaction provided by hydrolases, through changes in water structure, was detailed ( Perillo et al., 2023 ).

A central question related to these investigations concerns thermodynamics. Earlier works questioning the thermodynamic explanation for water-protein interactions ( Watterson, 1997 ), and how solid-state physics could help understand the behavior of hydrated proteins ( Teeter et al., 2001 ), found some echo in recent publications. First, free energies analyzed for four hydrated globular proteins differing by their net charges revealed that water was most stable around anionic residues, and least stable near hydrophobic residues ( Kalayan et al., 2023 ). As most biomacromolecules fold into chiral structures for their biological functions, how water molecules rearrange to minimize free energy at interfaces was shown, with achiral water molecules assembling in the first hydration shell of the protein into a chiral supramolecular structure with chirality transferred from the protein ( Yan et al., 2023 ). Applied to ribonuclease A, an ultra-high-resolution x-ray analysis structure exhibited a refined model based on two times more water molecules interacting with the protein, with thermodynamic implications ( Lisgarten et al., 2023 ).

More than 25 years ago, the unique properties of water molecules were recognized as being key players for protein-DNA interactions and molecular recognition ( Robinson and Sligar, 1998 ). Their hope for further biochemical and biophysical work was recently accomplished when the thermodynamics of water networks in protein cavities was investigated in the context of rational drug design ( Barros et al., 2023 ). The way water fine-tunes the 3D shape and dynamics of tumor-associated carbohydrate antigens was also nicely highlighted ( Bermejo et al., 2018 ). Investigations into water-protein interactions reported the role of water molecules in the activation of G protein-coupled receptors ( Hu et al., 2023 ). However, in the cell, water also serves as a substrate for proton transport. Accordingly, the role of water transport and proton release, for water molecules delivered to the catalytic center in photosystem II (PSII) was determined. This work led to an updated view of how ordered water molecules within the different channels contribute to catalyzing the light-induced oxidation of water into molecular oxygen ( Doyle et al., 2023 ). In the same field, in cytochrome c oxidase, the order and molecular dynamics of protonation in its two distinct channels and the number of water molecules required for proton transport were deciphered ( Gorriz et al., 2023 ). Finally, to improve our knowledge of the controlled diffusion of protons through transmembrane proteins, it was hypothesized that protons are conducted through dry apolar stretches by forming transient water wires ( Kratochvil et al., 2023 ).

3 Lessons from the oceans

Given the extraordinary life diversity in the oceans, these findings could inspire engineering for the coming decades, for example, in the design of new materials for industry and healthcare. In the case of the Photobacterium genus, which includes psychrophile and piezophile species living in symbiosis with marine organisms, an interesting study highlighted the role of cosolvent-water interaction in the modulation of bacterial luciferase functionality ( Lisitsa et al., 2023 ). The mechanism of light-driven water photooxidation of PSII isolated from the halotolerant green alga Dunasiella salina , revealed an unexpected level of conformational flexibility ( Caspy et al., 2023 ). In channel rhodopsins, the way the timing of the proton transfer was tightly controlled was investigated, showing how the number and location of water molecules close to the proton transfer groups had an impact on the proton transfer pathways ( Adam and Bondar, 2018 ).

For organisms living in the deep sea, a fundamental question concerns the effect of high hydrostatic pressure and how they adjust the volume changes of their biochemical reaction in cellulo ( Oliva et al., 2020 ). Adapting to extreme environmental conditions was initially analyzed in terms of the conformational stability of proteins ( Jaenicke and Závodszky, 1990 ). This question, later extended to the sub-seafloor and continental subsurface, led to investigations into the mechanisms driving molecular adaptation, through the stabilization effect of small molecules known as piezolytes, among which the most potent is trimethylamine N -oxide (TMAO). Using Fourier transform infrared (FTIR) spectroscopy combined with electronic-structure-based computer simulations, pressure-induced changes were connected to a locally enhanced H-bonding network at high compression ( Imoto et al., 2016 ). The effect of TMAO was then attributed to its large dipole moment, making it possible to form strong interactions with water molecules by forming H-bonds with at least three of these molecules, resulting in preferential hydration of the protein surface ( Kamali et al., 2022 ). Recently, this protective effect was extended to high temperature TMAO molecules binding very specific amino acids on the protein surface while other molecules ‘in a shell further away from the protein herd water molecules to enhance protein stability’ ( Boob et al., 2023 ). Finally, in nucleic acids, TMAO rescued the shift produced by high pressure in the conformational equilibrium of a DNA hairpin into the open, unfolded state ( Patra et al., 2018 ).

TMAO was found early in tissues from marine organisms ( Yancey et al., 1982 ). Although initially debated, the hypothesis that TMAO was adaptively regulated with depth in deep-sea teleosts progressively gained support ( Samerotte et al., 2007 ), and the highest TMAO contents in teleost marine fishes was found in Notoliparis kermadecensis , the deepest known fish in the southern hemisphere ( Yancey et al., 2014 ). Paul H. Yancey also mentioned that, although ‘TMAO can effectively counteract many inhibitory effects of hydrostatic pressure on numerous proteins’, ‘for vertically migrating marine animals, hydrostatic pressure stress responses are even more poorly characterized’ ( Yancey, 2020 ). Interestingly, his investigations connect with previous studies based on the combination of 1 H-NMR relaxometry and spectroscopy on the evolution of bound (‘structured’) water during the early development of turbot ( Psetta maxima ) ( Pouliquen et al., 1998 ) ( Figure 2 ). Our results could be reinterpreted in the light of reports confirming the presence of TMAO in extracts of juvenile turbot ( Hoerterer et al., 2023 ), and in oocytes of the common carp ( Cyprinus carpio ), showing increased TMAO levels with post-ovulation time ( Hajirezaee et al., 2021 ). The considerable variability we observed in the spin-lattice relaxation times of structured (unfrozen) water could be related to TMAO content changes, connected to its role in stabilizing protein structure during yolk protein proteolysis post-ovulation. Improvements in our understanding of the biophysical/biochemical parameters affecting fish egg hydration, and how piezolytes act, are also crucial in relation to buoyancy changes during their early embryonic development. In this field, the discovery of new aquaporins has provided insight into the molecular basis of the production of viable eggs ( Cerda, 2009 ). The multiple functions these channels have was extensively reviewed ( Cerda et al., 2017 ). Many efforts were also made to develop the theoretical basis for buoyancy variations in fertilized eggs, for example, applied to the Atlantic cod ( Gadus morhua ) ( Jung et al., 2014 ). The case of vertical distribution was examined for marine fish eggs; however, its importance is crucial across species and for many ecosystems given the impact of climate change ( Sundby and Kristiansen, 2015 ). Connected to lipid composition changes in the lipid sac and membranes of marine planktonic copepods, regulating buoyancy determines their seasonal life cycle, and in particular their vertical migration ( Pond et al., 2014 ).

Figure 2 . Examples of 1 H NMR investigations into the biophysical properties of structured (bound) water in experimental models relevant to marine biology and cancer research. Adapted from Pouliquen, D. et al. Comp. Biochem. Physiol. B (1998) 120, 715–726. doi: 10.1016/S0305-0491(9,810,067–6) and Pouliquen D., et al. Anticancer Res. (1993) 13, 49–56, with permissions. Both models presented a shift (horizontal red arrow) in the temperature corresponding to the minimum of the spin-lattice relaxation time (T1), meaning correlation times for the rotational motion τ R of unfrozen water molecules were decreased during the early development of turbot ( Psetta maxima ) embryos, and during rat liver carcinogenesis. A common increase in the activation energy for the rotational motion E R occurred in parallel. However, the two evolutions differed by the decrease (green vertical arrow) in the minimum of T1, only observed in the second case, which meant additional changes in the cross-relaxation parameters between water and macromolecular protons. Correlation times were calculated from the procedure described in the supplementary text of Pouliquen et al. (2006a) ( https://www-nature-com/articles/4401731#Sec18 ), Pouliquen, D., et al. Cell Death Differ. (2006) 13, 301–310. doi: 10.1038/sj.cdd.4401731.

One last issue concerns TMAO interactions with lipid membranes. A gel-to-fluid phase transition was observed, shifting to higher temperatures with increasing TMAO concentration, leading to a drastic water loss in the interlamellar space of fully hydrated multivesicular lipid assemblies ( Manisegaran et al., 2019 ). For some microorganisms living in deep-sea hydrothermal vents, the biophysical properties of archaeal membranes also revealed lower water permeability compared with that of n -acyl phospholipids, while remarkably, macrocyclization improved the membrane barrier to water ( Dannenmuller et al., 2000 ). The liquid-crystalline state that characterized their membranes, in addition to their low permeability, appeared to be an adaptation for living in a wide range of econiches, from cold ocean water to high temperatures and pressure in hydrothermal vents ( Chugunov et al., 2014 ).

4 Discussion

1 H-NMR investigations of marine fish eggs/embryos, and normal/neoplastic tissues identified changes in water state, revealing a common increased dynamics of structured water in early development and carcinogenesis. However, the normal-to-cancer transition involved specific additional changes in the cross-relaxation between water and macromolecular protons ( Figure 2 ; Pouliquen et al., 1993 ; 1995 ; 2001 ). These findings agree with differences observed in heat capacity in tumorous vs. normal tissues ( Vaupel and Piazena, 2022 ). Using QENS, considerable diversity was also observed in the flexibility of the different types of intracellular water in normal and cancerous cells ( Marques et al., 2020 ), while MR elastography highlighted its link with tumor fluidity ( Streitberger et al., 2020 ). Conversely, a fluid-to-solid transition characterized proliferative cells becoming dormant ( Munder et al., 2016 ). Differences in composition analyzed through simulations also revealed a shift in electron density of water in line with the lower stability observed in cancer vs. normal membranes ( Elfiky et al., 2023 ). However, other topics could benefit from transdisciplinary bridges between marine biology and cancer research, and vice versa . First, the role of TMAO in tumorigenesis, initially related to the anaerobic metabolism of Enterobacteriaceae ( Barrett and Kwan, 1985 ), is increasingly questioned, especially for colon cancer ( Duizer and de Zoete, 2023 ). However, TMAO directly drives an immunostimulatory phenotype in macrophages, supporting T cell responses, and reducing pancreatic ductal adenocarcinoma burden ( Mirji et al., 2022 ). Accordingly, in triple-negative breast cancer, TMAO activated CD8 + T cell-mediated immunity by inducing pyroptosis in tumor cells ( Wang et al., 2022 ). This topic thus requires much more investigation. Secondly, some aquaporins are prospective biomarkers of prognostic significance in prostate cancer ( Kushwaha et al., 2023 ), the role of aquaporin five in lung cancer beingalso questioned ( Jaskiewicz et al., 2023 ). Water exchange through aquaporin-4 being measured by MRI, transmembrane water-efflux rates are a biomarker of proliferative glioma ( Ruan and Keshari, 2022 ). MRI also allows to investigate damage to the myelin sheath, making it possible to study the different water pools in complex macromolecular environments ( van der Weijden et al., 2023 ). This, like MR microscopy ( Pooh et al., 2011 ), chemical exchange saturation transfer (CEST) MRI ( Maralani et al., 2023 ), or DW-MRI for determining microscopic tumor spread ( Shusharina and Nguyen, 2023 ), could increasingly benefit to marine biology, as shown recently ( Chanet et al., 2023 ; Sauer et al., 2023 ; Gerussi et al., 2024 ).

In conclusion, an increasing number of molecules isolated from oceans show interesting properties in oncology/immunology. Integrating the complex role of water molecules in the cell, and its changes during neoplastic transformation are expected, for better understanding molecular recognition and optimizing engineering-based drugs and materials. All questions relevant to water entropy, protein interactions, supramolecular rearrangement and membrane biology are also a huge domain, which could lead to many innovations in both disciplines.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics statement

Ethical approval was not required for the study involving animals in accordance with the local legislation and institutional requirements because too old reused data (already published in 1993 and 1998, with permissions).

Author contributions

DLP: Conceptualization, Writing–original draft, Writing–review and editing.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: water, biophysics, water-protein interactions, water channels, proton transport, membranes, marine biology, deep-sea biology

Citation: Pouliquen DL (2024) The biophysics of water in cell biology: perspectives on a keystone for both marine sciences and cancer research. Front. Cell Dev. Biol. 12:1403037. doi: 10.3389/fcell.2024.1403037

Received: 18 March 2024; Accepted: 29 April 2024; Published: 13 May 2024.

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Copyright © 2024 Pouliquen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Daniel L. Pouliquen, [email protected]

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Blood proteins ‘warn of cancer seven years before diagnosis’

It is hoped that in the future, the findings could be targets for cancer prevention..

Researchers have discovered proteins in the blood that could warn people of cancer more than seven years before it is diagnosed.

The scientists identified 618 proteins linked to 19 types of cancer including bowel, prostate and breast cancers.

Some 107 of the proteins were found in a group of people whose blood was collected at least seven years before diagnosis.

It is hoped the proteins could one day be targets for cancer prevention – instead of detection – and with further research lead to drugs to help stop the disease before it starts.

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The two Cancer Research UK-funded studies from Oxford Population Health suggest the proteins could be involved at the earliest stages of cancer, and could be linked to being at risk of the disease.

Some could be used to detect cancer earlier than is currently possible, potentially making it possible to treat the disease at a much earlier stage, or prevent it altogether.

Professor Ruth Travis, senior molecular epidemiologist at Oxford Population Health and a senior author of both studies, said: “To be able to prevent cancer, we need to understand the factors driving the earliest stages of its development.

“These studies are important because they provide many new clues about the causes and biology of multiple cancers, including insights into what’s happening years before a cancer is diagnosed.

“We now have technology that can look at thousands of proteins across thousands of cancer cases, identifying which proteins have a role in the development of specific cancers, and which might have effects that are common to multiple cancer types.”

Dr Iain Foulkes, executive director of research and innovation at Cancer Research UK, said: “Preventing cancer means looking out for the earliest warning signs of the disease.

“That means intensive, painstaking research to find the molecular signals we should pay closest attention to.

“Discoveries from this research are the crucial first step towards offering preventative therapies which is the ultimate route for giving people longer, better lives, free from the fear of cancer.”

In the first study, scientists analysed blood samples from UK Biobank taken from more than 44,000 people, including 4,900 who subsequently had a cancer diagnosis.

​The team used proteomics – the study of proteins to help learn how cancer develops and spreads – to analyse a set of 1,463 proteins from a single sample of blood from each person.

They compared the proteins of people who were later diagnosed with cancer and others who were not, allowing them to identify differences and establish which were linked to cancer risk.

The scientists also identified 182 proteins that differed in the blood three years before a cancer diagnosis.

​In the second study, the researchers looked at genetic data from more than 300,000 cancer cases to analyse which blood proteins were involved in cancer development and could be targeted by new treatments.

Some 40 proteins in the blood were found to influence someone’s risk of getting nine different types of cancer: bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney and malignant non-melanoma.

According to the findings, although altering these proteins may increase or decrease the chances of someone developing cancer, in some cases it may lead to unintended side-effects.

The researchers stress that further research is needed to find out the exact role the proteins play in cancer development, which are the most reliable ones to test for, what tests could be developed to detect the proteins in a clinic, and which drugs could target the proteins.

A test called the Galleri test is being trialled in the NHS, but it works by detecting tumour DNA circulating in the blood.

Researchers suggest the proteins they have discovered could be targets for cancer prevention.

Prevention and early detection are needed to keep improving cancer survival.

The findings are published in the Nature Communications journal.

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