1 in 8 cancer cases worldwide are caused by viral and bacterial infections

Serious stuff! Cancer is history (soon)!

"... These viruses, bacteria and other microbes are the focus of a new paper published Monday in The Lancet Oncology that linked an estimated 2.3 million new cancer cases in 2024 — 12 per cent of all new cases —  to these infectious agents.

A team of researchers at The International Agency for Research on Cancer (IARC), an arm of the World Health Organization, conducted the study. They found the largest number of cancer cases attributed to infections globally were caused by the bacterium Helicobacter pylori, which can increase the risk of stomach cancer and accounted for 760,000 cases, predominantly in eastern Asia. ...

For the first time, researchers linked even more cancers to infections, expanding their list to include 16 additional ones. ..."

From the abstract:

"Background

Infectious agents are an important preventable cause of cancer globally. To inform prevention efforts, we provide a comprehensive picture of cancer burden attributable to infections, including newly established, carcinogenic infectious agents and latest global cancer incidence estimates.

Methods

In this worldwide incidence analysis, we used data from the Global Cancer Observatory's Cancer Today (GLOBOCAN) database of cancer incidence in 2024 to estimate population-attributable fractions (PAFs), absolute numbers, and age-standardised incidence rates (ASIRs) of new cancer cases attributable to 12 infectious agents classified as Group 1 carcinogens by the IARC Monographs Programme:

Helicobacter pylori, human papillomavirus (HPV), hepatitis B (HBV) and hepatitis C viruses (HCV), Epstein–Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus, Schistosoma haematobium, human T-cell lymphotropic virus, Opisthorchis viverrini, Clonorchis sinensis, Merkel cell polyomavirus, and HIV. Estimates stratified by sex, country, and age group were aggregated by UN geographical subregion and World Bank income group.

Findings

An estimated 2·3 million new cancer cases were attributable to infections globally in 2024, which is equivalent to 12% of all cancer cases.

The largest number of cases was attributable to 

H pylori (n=760 000, PAF 4%), followed by 

HPV (n=750 000, 4%), HBV (n=360 000, 2%), 

EBV (n=260 000, 1%), and 

HCV (n=160 000, <1%).

The largest burden of infection-attributable cancer was in eastern Asia, with 990 000 cases (42% of the global total, ASIR 31·9 per 100 000 cases). ASIRs were also higher than the global average (22·7) in sub-Saharan Africa (28·5), central and eastern Europe (24·3), and southeastern Asia (23·1).

Focused analysis of EBV-attributable cancers revealed regional variation in the distribution of cancer types."

Global Health NOW: Fighting Fuels Yemen’s Health Crisis; and Bolstering Menopause Care Behind Bars

1 in 8 cancer cases worldwide is caused by infections, study suggests "Researchers estimate infections caused 2.3 million new cancer cases worldwide in 2024"

Global burden of cancer attributable to infections in 2024: a worldwide incidence analysis

Figure 1 ASIR of infection-attributable cancers per 100 000 person-years in 2024 for the six infectious agents with the most attributable cases

Scientists Identify Connection Between Nervous System and Aggressive Prostate Cancer

Good news! Cancer is history (soon)!

You wonder whether other cancers also manipulate the nervous system!

"A new study ... has found a link between the nervous system and the rapid development of neuroendocrine prostate cancer (NEPC), an aggressive form of the disease. ... the study found high levels of neuromedin U (NMU), a kind of neurotransmitter, present in prostate cells at the very early phase of NEPC formation, which support tumor progression by blocking the immune response. These findings could present a target for therapy for what is now a virtually untreatable disease. ..."

From the abstract:

"Neuroendocrine prostate cancer (NEPC) is an increasingly recognized, highly aggressive disease variant with no actionable therapeutic targets and a life expectancy of 7 months or less.

Using a transgenic mouse model, we now show that early stages of NEPC are associated with increased intraprostatic recruitment of Ly6G+ polymorphonuclear neutrophils (PMN) and reduced infiltration of CD8+ T cells. This coincided with expansive transcriptional changes of increased cell viability and cell migration, as well as upregulation of multiple neuronal mediators with the neuropeptide, Neuromedin U (NMU) as the top hit (Z score = 4.34; FDR < 5%; p = 3.62 × 10−9). Analysis of a large cohort of human patient samples revealed that NMU was highly expressed in early and late stage prostate cancer, preferentially segregating with AR-/NE+ metastases. Exposure of PMN to recombinant NMU was sufficient to stimulate cell migration, inflammatory gene expression with increased levels of the cytokine-like alarmin, S100A9 and suppression of T cell proliferation.

Genetic or pharmacological targeting of NMU/S100A9 signaling inhibited NEPC growth, reinvigorated an intratumoral immune microenvironment via recruitment of tumor antigen-specific CD8+ T cells with ‘stem-like’ (TCF1+/PD1+) and cytotoxic (GrzB+/KLRG1+) properties and enhanced the activity of therapeutic immune checkpoint inhibition, in vivo.

Therefore, NMU ‘innervation’ drives myeloid immunosuppression in NEPC and provides a therapeutic target to restore sensitivity to immunotherapy in this highly refractory malignancy."

Wistar Scientists Identify Connection Between Nervous System and Aggressive Prostate Cancer - The Wistar Institute

Neuromedin U ‘innervation’ reprograms myeloid immunosuppression in neuroendocrine prostate cancer (no public access)

‘Gamechanging’ Brain Tumour Test: Rapid Genomic Test Identifies Brain Cancer While Surgeons Operate

Good news! Cancer is history (soon)!

(234) ‘Gamechanging’ Brain Tumour Test: Rapid Genomic Test Identifies Brain Cancer While Surgeons Operate - YouTube

Virtual cell model predicts best cancer drug

Good news! Cancer is history (soon)!

Again Nature journal uses the horrible ideological term "people" instead of women!!!

triple-negative breast cancer (TNBC)

"A new ‘virtual cell model’ could help to choose more personalized treatments for women people with hard-to-treat triple-negative breast cancer. Researchers trained the prototype artificial-intelligence-based model, called ProteinTalks, on millions of protein measurements collected over time from breast cancer cell lines that were treated with dozens of antitumour drugs. The model did a good job of predicting how cells would respond to drugs it hadn’t seen before and also real-world clinical outcomes. “This is the first time that a virtual cell model goes out of the laboratory and is tested in a clinical scenario,” ...

In experiments using biopsies taken from individuals with TNBC, the virtual cell model showed promising results in identifying the same drugs that would prove to be effective when given to women people. The authors say this raises the possibility of more personalized care for TNBC, which accounts for 15–20% of breast cancer cases. ...

In their study, Guo and his colleagues aimed to develop a virtual cell model of breast cancer cells using proteomics data. They trained an AI model on more than 38 million protein measurements collected from 18 breast cancer cell lines, 16 of which were TNBC cells. The researchers treated the cells with 63 antitumour drugs that have been approved by the US Food and Drug Administration, and 59 drug combinations. ..."

From the abstract:

"Artificial intelligence-empowered virtual cell models represent an emerging approach for in silico drug discovery, yet most existing approaches lack large-scale, time-resolved perturbation proteomics data and interpretable frameworks for predicting therapeutic responses.

Here we generated more than 38 million temporal protein-abundance measurements from systematically perturbed breast cancer cell lines, and developed ProteinTalks, a virtual cell model.

Central to ProteinTalks is the synergy of this large-scale dynamic proteomic resource and the model architecture, enabling a new pretraining framework that learns transferable dynamical latent representations from temporal proteome trajectories. By modelling how proteins respond conditionally to different perturbations, this approach enables the model to function as an operational tool for diverse drug discovery tasks: predicting drug efficacy and synergy, discovering new drug combinations, probing proteins associated with drug resistance, stratifying patient responses and prioritizing drug candidates for patient organoids.

It also shows robust transferability, extending beyond cell lines to patient-derived organoids and clinical biopsies, generally achieving higher performance than the selected benchmark implementations under the evaluated protocols.

Together, ProteinTalks shows how scalable pretraining of transferable dynamic representations enables operational, dynamics-aware, proteomics-based virtual cell models to advance in silico drug discovery."

Nature Briefing: Translational Research

AI model predicts which breast-cancer drugs work best (behind paywall) "Model trained on millions of protein measurements can gauge drug effectiveness in tissue samples taken from people with triple-negative breast cancer."

An operational perturbation proteomics-based virtual cell model (no public access, but article above contains link to PDF)

A perturbation proteomics-based foundation model for virtual cell construction (preprint, open access)

Fig. 1 Overview of this perturbation proteomics study.

Fig. 3 Development and performance of the ProteinTalks model.

Scientists engineer ready-to-use cancer-fighting T cells for solid tumors

Good news! Cancer is history (soon)!

"Key takeaways

• ... researchers have developed a way to mass-produce cancer-fighting T cells from blood stem cells found in cord blood, engineered to target a protein found in many solid tumors — creating uniform batches instead of custom treatments for each patient.
• This way, scientists ensure that all the T cells they produce carry the same single tumor-targeting receptor, avoiding the random receptors that can attack healthy tissue and cause a dangerous condition called graft-versus-host disease.
• In mouse models of ovarian cancer and melanoma, a single dose kept tumors in check and extended survival, outperforming conventional donor T cells, which caused toxic side effects in the same tests.

...

Rather than starting with mature, donor-derived T cells, the researchers began a step earlier — with blood stem cells found in cord blood, which naturally give rise to every type of blood and immune cell. They then added a gene for a receptor that targets NY-ESO-1, a protein found in many solid tumors. Fragments of NY-ESO-1 get pushed to the outer surface and displayed there, name-tag style. The researchers then grew these engineered stem cells into T cells in the lab. ...

“From a small number of cord blood stem cells, we can generate trillions of therapeutic cells — enough for thousands of doses — within about six weeks,” ...  “At an estimated $5,000 per dose, this approach would be far more accessible than today’s therapies.” ..."

From the highlights and abstract:

"Highlights

• HSPC-derived AlloESO-T cells enable scalable, feeder-free T cell manufacturing

• AlloESO-T cells overcome autologous complexity, HLA restriction, and donor variability

• AlloESO-T cells display tumor homing, durable persistence, and TCR/NKR dual targeting

• AlloESO-T cells show minimal GvHD/CRS risk and stable hypoimmunogenicity

Summary

Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability.

We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T (AlloESO-T) cells.

Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. AlloESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors.

Relative to PBMC-derived counterparts, AlloESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion.

They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived AlloESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of AlloESO-T cells across solid tumors."

UCLA scientists engineer ready-to-use cancer-fighting T cells for solid tumors | UCLA "A new stem cell-based platform produces uniform T cells that attack solid tumors two ways while avoiding a dangerous side effect"

Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors (open access)

Graphical abstract

Figure 1 Generation and characterization of Allo/15ESO-T cells

Chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression

Good news! Cancer is history (soon)!

"Type II interferon (IFN-II) normally activates the immune system to fight cancer. However, prolonged IFN-II exposure can promote an immunosuppressive tumor environment that supports cancer growth, a confounding factor in cancer therapies. Johnson et al. explored why IFN-driven inflammation can be tumor suppressive in certain contexts but tumor promoting in others.

Chronic IFN-II stimulation unveiled secondary protumorigenic type I IFN (IFN-I) signaling that increased production of prostaglandins, bioactive lipids that inhibit anticancer immune responses.

Suppressing prostaglandin synthesis restored the ability of the immune system to attack tumors and reversed resistance to immunotherapy in melanoma cells.

The IFN-II–mediated IFN-I response was instigated by the release of mitochondrial RNA that activated innate immune signaling.

Timely inhibition of IFN-I signaling or blocking mitochondrial RNA release may therefore provide a means to promote antitumor immunity."

"Highlights

• ... researchers identify what flips a molecular “switch” that causes anti-cancer interferon activity to transition into pro-cancer activity, a longstanding mystery in cancer biology
• Chronic interferon activates a mitochondrial signaling pathway that, when turned off, effectively reverses tumor growth and immunotherapy resistance in a mouse model of melanoma
• The study could reveal new therapeutic targets to sustain anti-tumor immune responses

..."

From the abstract:

"Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells.

Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system.

In this study, we sought to determine the cellular mechanisms underlying this switch from antitumorigenic to protumorigenic interferon activity.

We show that chronic type II interferon (IFN-II) exposure distinctively induced tumor growth by activating a type I interferon (IFN-I) response mediated by release of double-stranded mitochondrial RNA (ds-mtRNA) into the cytoplasm. This IFN-I signal synergized with IFN-II to enhance tumor growth by increasing immunosuppressive prostaglandin E2 (PGE2) synthesis through increased cyclooxygenase 2 expression.

Elimination of PGE2 synthesis in immunotherapy-resistant melanoma cells restored their responsiveness to anti-PD1 treatment, indicating that this covert mtRNA-IFN-prostaglandin pathway could be a therapeutic target to combat immunotherapy resistance."

In Science Journals | Science

Why does the immune system sometimes help tumors grow? (original news release) "Salk Institute researchers define how chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression in mice, revealing a key target to sustain anti-tumor immune responses and combat immunotherapy-resistant cancer"

Chronic type II interferon promotes tumor growth through mitochondrial RNA–induced type I interferon and prostaglandin synthesis (no public access)

Representative images showing mitochondrial RNA (mtRNA) transcripts (red) present outside of the confines of mitochondria (cyan) in a melanoma cell following chronic interferon II exposure. Arrows point to specific examples of mtRNA outside the mitochondria.

Cancer cells release antioxidants to prevent immune cells from destroying them

Good news! Cancer is history (soon)! Are we finally cracking the secretes how cancer survives/counteracts immune responses and immunotherapy? 

"Now, scientists have discovered that certain immune cells depend on these very molecules to activate and destroy cancer cells, and that tumours exploit this dependency by releasing natural antioxidants to shut down the immune attack. ...

A team ... analysed the fluid surrounding cells within tumours grown in mice and found that cancers chemically ‘smother’ T cells, stopping their activation and preventing them from destroying cancer cells.

Tumours do this by releasing large amounts of a protein that is a natural antioxidant, Peroxiredoxin 1 (PRDX1), which mops up reactive oxygen species and deprives T cells of the activating signals they need to perform cancer killing.

Next, the team used CRISPR gene-editing technology to create mouse cancer cells that could no longer make the antioxidant protein. They found that removing the capacity for the cancer cells to produce the antioxidant promoted immune-cell activity and limited tumour growth. 

Finally, the team looked for the same mechanism in people. They analysed published data on the proteins released by human cancer cell lines, examined gene activity across thousands of human tumours, and isolated the fluid surrounding tumours removed from patients. All three approaches pointed the same way: human cancers also release PRDX1 into their surroundings, where it can strip away the reactive oxygen species that T cells depend on. ...

The findings also carry broader implications. Several large randomised clinical trials have found that antioxidant supplements fail to reduce cancer risk ..."

"New research reveals a promising new target for treating cancer by harnessing a type of molecule previously thought to do more harm than good.

For decades, reactive oxygen species, or ROS, often called free radicals, have been viewed primarily as harmful molecules linked to aging, DNA damage and cancer. A new study ... finds that cancer-fighting T cells need small amounts of ROS to attack tumors.

The investigators discovered that cancers exploit the T cell need for ROS by releasing an antioxidant protein that removes ROS from the tumor environment, effectively shutting down the attack by the immune system upon the cancer. ..."

From the editor's summary and abstract:

"Editor’s summary

Reactive oxygen species (ROS) have a paradoxical role in cancer.

Low to moderate ROS levels can stimulate tumor growth, whereas excessive ROS accumulation triggers oxidative stress and DNA damage.

Antioxidant therapies aim to neutralize free radicals and reduce oxidative stress, but clinical trials have not (yet) demonstrated improved cancer survival. Wesolowski et al. report that tumors can turn ROS dependency against the immune system, suppressing T cells and escaping antitumor immunity. 

Cancer cells secrete antioxidant enzymes, including peroxiredoxin 1 (PRDX1), into the extracellular space, depriving T cells of ROS needed for T cells to attack tumors effectively.

Removing PRDX1 from cancer cells restored antitumor immunity and made otherwise resistant tumors sensitive to checkpoint blockade immunotherapy.

These results suggest that targeting extracellular redox mechanisms could enhance the efficacy of immunotherapy.

Abstract

Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes.

Emerging data suggest that T cells depend on ROS for signal transduction. 

In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell–mediated antitumor immunity.

The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor–driven kinase signaling and effector function.

Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses.

These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention."

Cancer cells release antioxidants to prevent immune cells from destroying them | University of Cambridge (original news release 1) "Molecules called reactive oxygen species, which include so-called 'free radicals', have long been viewed as damaging byproducts of our body’s metabolism – a reason why antioxidant supplements have been considered as a potential way of reducing cancer risk."

Cancer cells use antioxidant protein to suppress T cells, resist immunotherapy, study finds (original news release 2) "OHSU co-author helps identify potential therapeutic target in tumors that evade the immune system"

Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species (no public access)

Killer T cells surrounding a cancer cell

New mRNA immunotherapy eliminates pancreatic tumors in mice

Good news! Cancer is history (soon)!

"... have developed an immunotherapy using a cocktail of messenger RNAs (mRNA) that could potentially transform pancreatic cancer treatment.

The study ... combines immune cytokine and tumor-associated antigen mRNAs into a single injection to treat pancreatic ductal adenocarcinoma.

Approximately 50% of mice with pancreatic cancer treated with the mRNA immunotherapeutic cocktail had complete tumor responses and, more impressively, remained disease-free for a year, even after treatment had stopped. 

"It's unheard of to get a response like this in these models of pancreatic cancer," ..."

From the abstract:

"Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses.

Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC.

Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models.

Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose.

Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence.

These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC."

New mRNA immunotherapy eliminates pancreatic tumors in mice

mRNA immunotherapy developed by UMass Chan scientists eliminates pancreatic tumors in mice (original news release)

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer (open access)

Fig. 2: A multiplexed cytokine mRNA cocktail mobilizes innate and adaptive immunity and reduces tumor growth and desmoplasia in “cold” PDAC-bearing mice.

Fig. 3: Combinatorial cytokine mRNA therapy can achieve robust cytotoxic T cell immunity in a “hot” PDAC model after a single dose.

Scientists Identify Fructose as a Surprise Driver of ovarian Cancer Spread

Will this be the end of fructose in soda drinks? Don't bet on it! 😊

Wistar Scientists Identify Fructose as a Surprise Driver of Cancer Spread - The Wistar Institute "A new study from The Wistar Institute has uncovered an unexpected link between fructose — a common dietary sugar — and the spread of an aggressive form of ovarian cancer. Published in Nature Aging, the study found that cancer cells not killed by chemotherapy send signals to neighboring tumor cells, helping them become more capable of spreading. The researchers identified fructose as a key messenger in this process, revealing a previously unrecognized way that treatment-surviving cancer cells may promote the spread of cancer."

Mouth Microbes transmitted to gut Could Help Diagnose gastrointestinal Cancers

Amazing stuff! Cancer is history (soon)!

Is this maybe another good reason to do daily tongue scraping?

"... In a new study, researchers have shown that mouth bacteria migrate through the gastrointestinal tract in certain types of cancer.1 The findings raise hope that the breakdown of these carefully sectioned-off compartments in the body could be an indicator of disease, leading to easier and quicker diagnostic tests for gastrointestinal cancers. ..."

"... In a study ... researchers report that by analyzing the make-up of oral microbes, they may be able to detect signals associated with gastric (stomach) and colorectal cancer. These findings could lead to the development of new, less-invasive screening tests for gastrointestinal cancers. ...

To conduct the study, the researchers recruited 507 volunteers to donate both oral and fecal samples, using a highly standardized collection process. The cohort included 129 healthy individuals; 215 people with metabolic disorders such as metabolic syndrome, hypertension, hyperlipidemia, and type 2 diabetes; 77 people with gastric cancer; and 86 people with colorectal cancer. For the volunteers with cancer, samples were collected before the start of any treatment.  ...

The findings were more nuanced than a simple cancer-versus-healthy comparison. The MF index was significantly elevated in patients with gastric or colorectal cancer but not in people with metabolic disorders. After accounting for alcohol consumption, regular exercise, and BMI, the association remained robust for both gastric and colorectal cancers. ..."

From the highlights and abstract:

"Highlights

• Mouth and gut microbial compartmentalization is disrupted in gastrointestinal cancers

• Mouth-to-gut transmitted bacteria correlate with metabolic and inflammatory markers

• Oral-fecal transmission signatures enable cancer classification by oral microbiome alone

• Transmission-based classifier surpasses microbiota models and fecal occult blood testing

Summary

The human microbiome is spatially compartmentalized, yet oral bacteria can ectopically colonize distal sites such as the gut, potentially influencing disease.

By analyzing paired oral and fecal microbiomes from 507 participants across healthy controls and patients with metabolic disorders or gastrointestinal cancers, we established a quantitative mouth-to-feces (MF) index to measure MF microbial transmission.

The MF index revealed elevated mouth-to-gut transmission in cancer and a strong association with host metabolic and inflammatory indicators.

Using transmitted taxa, we developed a random forest classifier that accurately distinguished gastric/colorectal cancer from healthy controls across seven independent cohorts, even when trained solely on oral microbiome data.

When benchmarked against the conventional screening test, the MF-based model achieved markedly higher sensitivity than the fecal occult blood test.

These findings uncover disease-specific transmission signatures and highlight MF microbial profiling as a generalizable, non-invasive framework for gastrointestinal cancer diagnosis and risk stratification."

Mouth Microbes Could Help Diagnose Gastric Cancers | The Scientist "Some mouth bacteria migrate to the gut in gastrointestinal cancers, opening possibilities for more convenient cancer diagnostic tests."

Mouth and gut microbes could help detect gastrointestinal cancers

Mouth-to-gut microbial transmission signatures enable robust, non-invasive diagnosis of gastrointestinal cancers (open access)

Graphical abstract

Figure 2. MF transmission index as an assessment of the mouth-gut microbiome axis

New biobank of patient-derived tumour organoid 3D models reveals cancers’ weak spots of five different cancer types

Good news! Cancer is history (soon)! This could be a major advance!

"... The biobank is expected to have wide utility, enabling scientists to identify the genes that specific cancers depend on for growth, revealing potential weak points that could be targeted with future treatments.

The study is published alongside two complementary papers from international collaborators, reflecting a wider multi-year effort to refine organoid models and make them more accessible to the research community.

For decades, cancer researchers have relied on two-dimensional (2D) cell lines to study cancer. These workhorse models, in which cells are grown in a flat layer on laboratory plates, have provided important insights into cancer biology and remain widely used.

However, 2D models have limitations: they do not fully capture the diversity and complexity of tumours seen in patients and they have adapted to laboratory conditions over time. Researchers are therefore increasingly looking to develop next-generation models that better reflect tumours found in patients, such as organoids, to complement 2D cell lines and help address some of these gaps. ...

In a first of its kind study in organoids, the researchers went on to use CRISPR screening, a method they used to systematically switch off genes one by one to see if the cells survived, in order to map the genes that are critical to cancer cell survival across 162 of the organoid models. They identified thousands of genetic dependencies, including both common genes required by many cancers to survive, and more specific vulnerabilities linked to particular tumour types. ..."

From the abstract:

"Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture.

Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines.

Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models.

Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR–Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples.

In colorectal cancer, functional and pharmacological interrogation of the EGFR–RAS–MAPK axis uncovered differential effects of KRAS variant alleles.

This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology."

New biobank of tumour models reveals cancers’ weak spots "The largest characterised collection of patient-derived tumour organoids to date is helping scientists identify the genes cancers need to grow and survive."

A tumour-derived organoid biobank maps cancer gene dependencies (open access)

Fig. 1: Establishment of organoid biobank and patient-linked clinical data.

Fig. 2: Genomic features are conserved between organoid and patient-matched tumour.

Hidden drivers of aggressive childhood cancer revealed

Good news! Cancer is history (soon)!

"New insights into why some children with rhabdomyosarcoma (RMS) develop aggressive disease despite being classified as non-high-risk have been uncovered. ...

RMS is broadly split into two different types, depending on whether the tumour contains a genetic risk marker. This marker is a fusion of two genes that are not normally connected. In patients with this marker, survival is substantially lower than in those who do not carry it, despite intense treatment.2

However, some children whose tumours do not carry the high-risk marker still develop aggressive disease, and it is unclear why this happens.

In a new study, researchers ... sought to understand why this group of non-high-risk patients go on to experience such an aggressive cancer. ...

In particular, they used single-cell RNA sequencing, which is a technique that allowed the team to examine gene activity in individual cancer cells. This revealed the true aggressive face of cancer cells that had ordinarily been classified as non-high-risk.

The team also used a method called spatial transcriptomics, which enabled the scientists to map where the cancer cells were located within the tumour, revealing how aggressive cell populations are organised within the cancer tissue.

The study revealed that aggressive tumours of children who had been classified as non-high-risk have gene expression patterns that closely resemble those of high-risk tumours, despite lacking the genetic risk marker.

They also found that children with non-high-risk tumours which behaved aggressively carry rare genetic changes that affect the same cellular pathway as high-risk tumours. This suggests that there are multiple genetic routes leading to the same aggressive tumours. ..."

From the abstract:

"Somatic mutations often predict survival in childhood cancers, as exemplified in rhabdomyosarcoma (RMS), in which FOXO1 gene fusion status is a key prognostic feature.

In this study, we examined single-cell transcriptomes and discovered that cancer cells of lethal disease converge on a common cell state with a shared transcriptional landscape, irrespective of fusion status.

Nuclear transcriptomics, chromatin accessibility, spatial transcriptomics, perturbation studies, and previously published datasets validated the overarching high-risk cell state.

The convergent cell state only partially overlapped with transcriptional effects of the FOXO1 fusion and unexpectedly exhibited neural features.

Overall, these findings delineate a cell state of high-risk RMS cells that transcends conventional molecular and histologic boundaries, suggesting an overarching disease phenotype that could transform target discovery and inform clinical practice."

Hidden drivers of aggressive childhood cancer revealed "New clues have been uncovered about why the childhood cancer, rhabdomyosarcoma, may behave aggressively. "

High-Risk Rhabdomyosarcomas Feature a Convergent Cell State (open access)

Brain cancer cells exploit normal nerve signaling to multiply and invade, new study finds

Amazing stuff! Cancer is history (soon)!

"... Many gliomas arise from, or contain cells that closely resemble, oligodendrocyte precursor cells (OPCs), which are immature support cells in the brain. These OPC-like cells are a major part of tumors such as glioblastoma (GBM) and H3K27M-altered diffuse midline glioma (DMG). What makes this especially interesting is how closely glioma cells mirror healthy OPCs, sharing many of the same biological behaviors. ..."

From the abstract:

"Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity that functions as a paracrine factor crucial for glioma growth.

Here we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterparts.

NLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2) on both glioma and healthy oligodendrocyte precursor cells (OPCs), facilitating CSPG4 shedding by ADAM10.

NLGN3–CSPG4 interactions alter membrane tension, thereby activating mechanotransducers, primarily PIEZO1, leading to membrane depolarization and subsequent ADAM10-mediated CSPG4 shedding.

The NLGN3–CSPG4–PIEZO1 pathway maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring its dual roles in healthy and malignant contexts."

Brain cancer cells exploit normal nerve signaling to multiply and invade, new study finds

It appears there is no original news release about this research by any of the involved institutions.

Neuroligin-3–CSPG4 interaction maintains oligodendrocyte precursor cell progenitor state and promotes glioma proliferation through mechanotransduction (open access)

Scientists Identify New Mechanism Behind Chemotherapy Resistance in Ovarian Cancer

Good news! Cancer is history (soon)!

"... identified a new mechanism behind the chemotherapy resistance that makes ovarian cancer so lethal.

In a new study ... the researchers showed that chemotherapy triggers an inflammatory cascade that recruits immune cells into the tumor microenvironment, which ultimately function to protect the cancer from subsequent chemotherapy. Notably, this finding could improve outcomes for patients because the molecular pathway the researchers discovered has the potential to be blocked using drugs already in clinical use for other diseases. ...

The researchers also see a possible opening for combination approaches involving immune checkpoint inhibitors, which reawaken the T cells. If T cell suppression by neutrophils turns out to be a major contributor to chemoresistance, pairing checkpoint inhibitors with IL-1β-targeted therapy could offer another route to restoring chemotherapy’s effectiveness. ..."

From the abstract (This abstract is not easy to read, too much technical jargon, written for experts only!):

"Background

High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and cell-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis.

Previous work suggests that chemotherapy induces immunological changes in the tumor microenvironment (TME). However, experimental evidence for how such chemotherapy-induced TME remodeling modulates the response to ongoing chemotherapy remains poorly documented in HGSC.

Methods

We analyzed paired pre-chemotherapy and post-chemotherapy HGSC bulk transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets to identify chemotherapy-induced tumor-extrinsic factors and their cellular sources in the TME.

To test causality, we used chemoresistant, homologous recombination-proficient murine metastatic HGSC models with deficiencies in the interleukin 1 beta (IL1β) pathway (IL1β–interleukin 1 receptor type 1 (IL1R1) axis).

Flow cytometry and scRNA-seq of omental tumors were used to define cellular interactions.

Contributions of neutrophils and neutrophil extracellular traps (NETs) were assessed by antibody-mediated depletion and immunofluorescence.

Direct effects of IL1β and NETs on cancer cell chemosensitivity were tested in vitro. Finally, paired pre-chemotherapy and post-chemotherapy omental HGSC specimens from patients were analyzed for neutrophil infiltration and NET formation.

Results

In HGSC datasets, post-chemotherapy tumors exhibited increased IL1β expression with myeloid cells identified as the primary source.

In chemoresistant murine models, chemotherapy increased neutrophils and NETs in omentum tumors in wild-type mice. These increases were abrogated in IL1β-deficient mice, which showed a shift toward an effector-like CD8+ T-cell state and improved tumor control.

Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1β-deficient mice.

In vitro, IL1β did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Furthermore, scRNA-seq and flow cytometry revealed that IL1R1 was predominantly expressed by tumor-associated fibroblasts.

Consistently, IL1R1-deficient mice exhibited increased chemosensitivity, with decreased neutrophil accumulation and increased IFNγ+TNF+CD8+ T cells. Additionally, we found that chemotherapy upregulated the neutrophil chemoattractant C-X-C motif chemokine ligand 2 (CXCL2), and disruption of the IL1β–IL1R1 axis decreased CXCL2 levels in tumor-associated fibroblasts.

Finally, residual human HGSC tumors after chemotherapy showed increased neutrophils and a trend toward increased NETs.

Conclusions

We demonstrate that chemotherapy-induced IL1β-dependent neutrophil accumulation drives chemoresistance in HGSC. This study provides experimental evidence that chemotherapy-induced inflammation contributes to chemoresistance and highlights the potential of targeting this pathway to overcome chemoresistance in HGSC."

Wistar Scientists Identify New Mechanism Behind Chemotherapy Resistance in Ovarian Cancer - The Wistar Institute

Chemotherapy induces an IL1β-dependent neutrophil recruitment and activation that promote chemoresistance in metastatic ovarian cancer (open access)

Fig. 4 T-cell suppression and NETs may contribute to the IL1β-neutrophil-induced chemoresistance.

Very rare, transmissible cancer in a lake fish observed

Amazing stuff! Cancer is history (soon)!

"The mystery disease that’s been plaguing the brown bullhead catfish (Ameiurus nebulosus) in a lake straddling the Canada–US border has been identified as a type of transmissible cancer — a phenomenon rarely seen in the animal kingdom.

Surveys have suggested that the disease, a type of melanoma that manifests as inky black skin lesions, affects around one-third of the lake’s catfish population. But it appears in both young and old individuals, suggesting that it might not cause a rapid death."

"Researchers have discovered a contagious cancer in catfish — just the fourth example of tumour cells that spread naturally from one animal to another. ...

The skin lesions, a form of melanoma, are inky black and sometimes crusty, with some fish displaying “tumours on top of tumours”, and can spread to the brain, liver and other organs ... But the health effects are unclear, because the tumours appear in young and old mature fish. “We don’t have evidence of a huge age cliff that suggests it’s killing the fish,” ... "

"... In fact, the first documented observation of the catfish cancer may be from Massachusetts, in the journals of Henry David Thoreau.

In July of 1852, Thoreau was on the Concord River and wrote, “one of these large pouts [catfish] had a very large velvet-black spot, which included the right pectoral fin; a kind of disease I have often observed on them.”

Six years later, Thoreau again wrote in his journal: “I see a pout this afternoon in the Assabet”—a tributary of the Concord River— “lying on the bottom, near the shore, evidently diseased. He permits the boat to come within two feet of him. Nearly half the head, from the snout backward diagonally, is covered with an inky-black kind of leprosy, like a crustaceous lichen.” ..."

From the abstract:

"Since 2012, brown bullhead catfish (Ameiurus nebulosus) in a lake that spans Vermont, USA, and Quebec, Canada, have shown a high rate of melanomas, suggesting a causal contaminant or contagion.

We tested the hypothesis that this affliction represents a clonally transmissible cancer, a rare phenomenon in which cancer cells themselves spread between individuals, behaving more like parasites than conventional tumours.

Whole-genome sequencing of tumour and matched non-tumour host tissues revealed that tumour mitochondrial and nuclear genomes are more closely related to each other than to their hosts or unaffected fish.

Hundreds of thousands of genetic variants are shared among tumour samples but are absent from host fish, vastly exceeding levels seen in conventional cancers. These findings indicate that melanoma in these brown bullheads represents the fourth documented type of naturally occurring transmissible cancer in animals, after dogs, Tasmanian devils and several bivalve species. This raises important questions about the cancer’s origin, the mode of transmission and the long-term impact on fish populations."

Nature Briefing: Cancer

Rare contagious cancer discovered in wild catfish "Transmissible tumours have been found in only a few types of animal, but there might be many more out there."

More Like Parasites Than Tumors: Vermont Scientists Discover Transmissible Cancer in Catfish (original news release)

Brown bullhead catfish melanoma represents a novel transmissible cancer (open access)

Fig. 1: Brown bullhead sampling, example melanistic lesions and hypotheses of tumorigenesis.

How Inherited genetic differences set the stage for cancer progression investigated by repeated, controlled experiments

Amazing stuff! Cancer is history (soon)!

"Whether mice respond to environmental exposures by developing mutations and cancers strongly depends on their genetic makeup at birth.

Researchers bred four strains of mice with different levels of genetic susceptibility to liver cancer and then exposed them to the same carcinogen. The rate and progression of liver cancer was strongly influenced by the animals’ genetic background. The research might help explain why some people develop cancer when exposed to carcinogens such as cigarette smoke while others don’t."

"... In a study in mice, researchers found that genetic ancestry directly influences how cancer-causing mutations behave and how the resulting cancers grow and interact within the body. 

Uncovering why and how cancer behaves in different people is crucial to support the use of personalised medicine, which aims to tailor treatment to a specific patient for better outcomes, experts say. ...

Controlled experiment 

To understand the role of genetics, researchers from the universities of Edinburgh, Cambridge, Heidelberg and Yale recreated cancer development under controlled conditions.

Using four genetically distinct groups of mice, representing levels of genetic variation similar to those seen in human populations, the team exposed each group to the same DNA-damaging chemical comparable to those found in some processed meats. 

They then tracked how tumours developed in remarkable detail, analysing whole genomes, gene activity, and tumour structure.

Despite identical exposure, the cancers that emerged followed strikingly different paths depending on genetic background. ..."

From the abstract:

"Human cancers are heterogeneous. Dissecting how germline genetic variation and environmental factors shape tumour evolution using human datasets is limited by inherent diversity in genetic backgrounds and environmental exposures.

Here, to overcome these limitations, we re-ran early tumour evolution hundreds of times in diverged inbred mouse strains, generating matched histology and whole-genome and transcriptome sequences.

The sex, environment and carcinogenic exposures were all controlled, and the study design allowed us to capture genetic variation comparable with that observed across human populations while exploiting the nested hierarchical structure of strain–litter–animal–tumour relationships.

Our analyses reveal that epistatic interactions between genetic background and acquired somatic mutations result in population-specific disease progression, including choice of driver mutations, occurrence of whole-genome duplication and subclonal selection dynamics that mirror both cancer susceptibility and tumour growth rate.

Even modest genetic divergence, comparable with that found across human ancestry groups, can strikingly alter selection pressures during cancer development to shape both cancer risk and the trajectory of tumour evolution."

Nature Briefing: Cancer

Background genetics and new mutations interact to direct cancer evolution (behind paywall) "Rerunning tumour evolution in mice shows how cancer develops after DNA damage and reveals that background genetics and acquired mutations interact to shape genome stability and selection. This provides experimental evidence that genetic ancestry has an important role in setting the trajectory of cancer evolution."

New clues to long-standing cancer mystery (original news release) "Inherited genetic differences play a crucial role in determining how cancers develop and evolve after DNA damage, a major international study suggests."

Study reveals why DNA damage from smoking and UV rays may cause cancer in some people but not others (original news release) "Scientists have found the first direct evidence of the powerful role our genetic makeup plays in influencing our risk of cancer, with inherited genes interacting with acquired genetic mutations to shape how tumours evolve."

Genetic background sets the trajectory of experimental cancer evolution (open access)

Fig. 1: Cancer susceptibility and mutagenesis are shaped by germline genetic variation.

How some lung cancer tumors hijack the nervous system

Good news! Cancer is history (soon)!

"Highlights

• Cachexia, a syndrome marked by unwanted weight loss, sickness, and loss of appetite that accompanies and amplifies chronic illness, affects roughly half of all cancer patients and is responsible for a quarter of all cancer deaths
• ... discovers that some lung cancer tumors can induce cachexia by communicating directly with the brain using a lipid signaling molecule—hijacking the nervous system and impacting behavior
• Findings suggest that tumors affect the peripheral nervous system and dietary changes could be used to treat cachexia and improve outcomes in lung cancer patients

...

According to the Cleveland Clinic, a quarter of cancer deaths can be attributed to one source: cachexia. ...

The researchers found that a common genetic subset of lung cancer is more prone to cachexia and that tumors from this subtype talk to the brain through sensory neurons in the lung.

Silencing these sensory nerves to disrupt the tumor-to-brain connection reduced cachexia, as did blocking the production of the lipid signaling molecule prostaglandin E2 (PGE2) through dietary changes. ..."

From the abstract of the perspective:

"Cachexia—a progressive loss of body mass despite adequate nutrition—is one of the most devastating consequences of cancer.

However, its causes are incompletely understood. Increased energy expenditure can contribute to cachexia, but “sickness behaviors,” such as loss of appetite (anorexia), fatigue, reduced activity, and malaise, also often play a part.

Several tumor-derived inflammatory molecules act on the brain and peripheral tissues to promote cachexia in some contexts , but targeting these factors has not yet led to effective cachexia treatments.

On page 90 of this issue, Cross et al. report that mouse lung tumors bearing mutations in serine/threonine kinase 11 (Stk11, also known as Lkb1) activate vagal sensory neurons through local inflammatory lipid signaling.

Notably, a high-fat diet intensifies these sensory nerve signals from the tumor to modulate the brain circuits that control feeding behavior. This mechanism promotes anorexia and cachexia."

From the editor's summary and the abstract:

"Editor’s summary

Cancer cachexia is a complex metabolic syndrome marked by reduced appetite, weight loss, and muscle wasting. Cross et al. report that a subset of Lkb1-mutant lung cancers is prone to cachexia ... When mice were fed a high-calorie, high-fat diet, reduced appetite and weight loss were observed, which was associated with reduced appetite sensing to the brain.

Prostaglandin E2 (PGE2) is a lipid-signaling molecule produced by tumors that increases when animals consume fat.

The authors found that PGE2 acts locally in the lung to drive decreased weight and appetite.

Blocking either PGE2 production or silencing sensory nerves reduced cachexia, suggesting that the peripheral nervous system may represent a therapeutic target. The observations further suggest that tumors can trigger cachexia through local nerve signaling, as opposed to only circulating factors. ...

Abstract

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients.

We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer.

In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness.

We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia.

Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia.

Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia."

Are lung cancer tumors hijacking the nervous system? - Salk Institute "New Salk scientist finds that lung cancer tumors talk directly to the nervous system to exacerbate disease-related wasting, revealing a potential target for new therapeutics"

Local signals, systemic decline (Perspective, no public access) "A high-fat diet affects tumor-to-nerve signaling and promotes cachexia in mice"

A dietary switch promotes sensory neuron–dependent cancer-associated cachexia