Highlights in Cancer Research: July 2025

Pancreatic cancer arises from cells carrying genetic mutations in oncogenic KRAS. We discovered that the pancreas protects against disease by actively eliminating KrasG12D-expressing cells. This suggests that for cancer to start, KrasG12D cells must override cell elimination mechanisms to survive in tissues. However, what controls whether mutant cells are eliminated or survive has remained unclear.

Here, we found that not all KrasG12D cells are eliminated from the pancreas, suggesting some cells have a survival advantage. We discovered that surviving cells switch on genes that regulate cell dormancy, stem and progenitor cell fates and non-canonical Wnt signalling in vivo. Using RAS-normal coculture assays, we showed that Wnt5a increases E-cadherin-based cell-cell adhesions at normal-mutant cell-cell boundaries, allowing RAS cells to stay in the epithelium. This is reversed upon WNT inhibition, suggesting WNT signalling is required to keep RAS cells attached to normal neighbours and prevent mutant cell expulsion. We showed that WNT signalling is active, and E-cadherin-based cell-cell adhesions are increased at mutant-normal cell boundaries in vivo. Inhibition of WNT in vivo caused a loss of KrasG12D cells from the pancreas. In addition, human data revealed increased WNT5A expression in pancreatic cancer precursor lesions. Thus, WNT5A signalling is required to promote E-cadherin-based cell-cell adhesion between mutant cells and normal neighbours, boosting mutant cell survival.

Our data show that genetic mutations alone are insufficient to induce cancer and suggest that when present in adult tissues in low numbers, cell survival is an essential first step. Future work will unravel the additional cues mutant cells need to avoid tissue defence mechanisms and progress from a dormant-like state to precancerous lesions. A better understanding of these very early stages is critical for the development of early detection and prevention cancer strategies.

The study of tumorigenesis and tumour progression relies on modelling cancer development and progression in preclinical models. While advances in gene editing over the past few decades enabled engineering tumour models for a wide range of gain- and loss-of-function mutations, other frequent mechanisms involved in oncogene activation, such as focal amplifications, are underexplored due to the lack of appropriate tools.

In this paper, Pradella et al. developed a method to induce, track and engineer the formation of oncogenic ecDNAs. The method is based on Cre- LoxP recombination and uses two inducible fluorescent markers: mScarlet and GFP, whose expression is induced upon recombination. In this system, mScarlet is linked to the linear chromosome, and GFP is linked to the circularizable fragment, allowing the identification of successful tandem duplication by the double fluorescent label. Further on, the authors provide proof of concept for the use of this system both in vitro (MDM2 oncogene in HCT116 cells) and in vivo (MDM2 and Myc genes in mice), showing that the GFP fluorescence could act as a semiquantitative measure of ecDNA abundance and a marker of ecDNA loss. The authors also show that engineered ecDNAs harbour the ability to immortalise primary cells, effectively inducing malignancy upon additional HRAS^G12V transduction or transfection with MYC transgene.

This study has uncovered emerging cellular networks that evade the immune system activity within the brain metastatic microenvironment, thereby limiting the efficacy of immunotherapy in symptomatic brain metastases.

We addressed the heterogeneity of astrocytes -key players in the progression of brain metastases- and identified a novel immunosuppressive axis. Specifically, we found that STAT3⁺ astrocytes secrete a molecule called TIMP1, which acts on CD8⁺ lymphocytes via binding to CD63, a receptor enriched on the surface of activated immune cells. This astrocyte-derived signaling mechanism contributes to local immunosuppression, impairing the effectiveness of T cell-mediated anti-tumor responses.

Building on these findings, we successfully applied a combined immunotherapeutic strategy in multiple preclinical models as well as in patient-derived organotypic cultures. This approach involved systemic enhancement of T cell activation using immune checkpoint blockade in conjunction with the local inhibition of TIMP1-mediated immunosuppression.

Furthermore, we demonstrated that cerebrospinal fluid collected via liquid biopsy from patients with brain metastases exhibits significantly elevated TIMP1 levels compared to healthy controls. These findings highlight TIMP1 as a potential biomarker for patient stratification and therapeutic monitoring for this combined immunotherapy strategy.

Small-cell lung cancer (SCLC) is characterised by its high molecular heterogeneity. How this diversity contributes to its aggressiveness remains an open question. This study reveals that neuroendocrine (NE) cancer cells in SCLC not only resemble neurons in their transcriptomic profile, but also in their electrophysiological properties. These cells generate electrical signals, firing action potentials and propagating calcium waves, to promote tumour progression.

However, maintaining this electrical activity requires supplemental energy sources. NE cells exploit oxidative metabolism and rely on neighbouring non-NE cancer cells to supply lactate, much like neurons depend on astrocytes. This metabolic symbiosis fuels ATP production, which is required for the increased electrical activity in NE cells. Suppressing the electrical signals of NE cells, either indirectly by blocking lactate transport or directly by tetrodotoxin and chemogenetics, dramatically reduces tumour growth and metastasis both in vitro and in vivo.

Moreover, SCLC patients with higher levels of classic neuronal markers in their tumours had worse outcomes, suggesting that the electrical activity of cancer cells plays a key role in disease progression.

The discovery that electrical activity directly drives SCLC progression unveils a powerful vulnerability and opens electrifying new avenues for therapy by cutting these circuits and aiming to pull the plug on aggressive tumours.

Cancer-associated thrombosis are a major cause of morbidity and mortality in patients with cancer, especially at the metastatic stage. Yet, prevention of thrombosis remains an unmet clinical need due to the bleeding risk associated with routine anti-coagulant therapies and the absence of biomarkers predictive of thrombosis risk.

In this paper, Lucotti et al. have identified the existence of a pro-thrombotic niche (PTN) unique to the lungs of both pre-clinical models and patients with various cancers, including pancreatic, lung, and breast cancer. The PTN is molecularly and immunologically distinct to the pre-metastatic niche. Activated interstitial macrophages that are reprogrammed by tumor-derived C-X-C motif chemokine 13 (CXCL13) are the central component of the lung PTN and release pro-thrombotic small extracellular vesicles (sEVs) enriched in integrin β2. Combining single sEV dSTORM microscopy, photocatalytic proximity labeling technology, and Single Molecule Force Spectroscopy, the authors found that integrin β2 is present in its activated and clustered conformation on the surface of PTN-derived sEVs and forms active heterodimers with its ax partner, which in turn allows interaction with platelet GPIb, leading to clot formation. Notably, Lucotti et al. demonstrate that β2 can be targeted therapeutically in pre-clinical models of cancer, leading to reduced thrombotic events and, surprisingly, decreased metastatic burden, while avoiding excessive bleeding. Moreover, the authors detected higher levels of plasma sEV-β2 in pancreatic cancer patients prior to a thrombotic event compared with patients with no history of thrombosis.

Together, these findings provide a rationale for the use of β2 blockade as a dual anti-thrombotic and anti-metastatic therapy for cancer patients. Moreover, they point to sEV-β2 as a potential biomarker for early identification of patients at an increased risk of thrombosis, enabling clinicians to prioritize timely anti-coagulant intervention and reduce the likelihood of life-threatening events.

The peripheral nervous system (PNS) plays a critical role in pancreatic cancer biology, but its molecular interaction with tumors has remained largely unexplored due to the distant location of neuronal cell bodies from the tumor mass. We developed a method called Trace-n-Seq, which combines retrograde axonal tracing with single-cell RNA sequencing, enabling for the first time the molecular characterization of tumor-innervating neurons. By profiling over 5,000 individual neurons from healthy and pancreatic ductal adenocarcinoma (PDAC) tissue, we discovered that PDAC induces profound transcriptional reprogramming in sympathetic and sensory neurons, including the emergence of a distinct “cancer nerve signature.” These reprogrammed neurons engage in active crosstalk with cancer-associated fibroblasts and tumor cells, promoting tumor progression. Importantly, disrupting these neuronal inputs via pharmacological or surgical denervation sensitized tumors to immune-checkpoint inhibitors and reduced tumor growth. We also found that the widely used chemotherapy agent nab-paclitaxel inhibits mostly sensory neurons in PDAC innervating nerves which contributes to its therapeutic efficacy. Our study uncovers an unexpected, yet targetable dimension of the tumor microenvironment—cancer-induced neuronal remodeling.

Breast cancer (BC), the most prevalent cancer in women, is marked by heterogeneity in its presentation. Despite the availability of published cell lines, most studies revert to a limited amount of models, and more than half of them rely on MCF-7 cells, failing to recapitulate disease heterogeneity. This study presents the largest and most comprehensively characterized collection of orthotopic BC cell line-derived xenograft (CDX) models to date. Using both mammary intraductal (MIND) and fat-pad transplantation (FPT) approaches, the authors established CDX models from 20 human BC cell lines representing all major molecular subtypes. These models faithfully recapitulate the full spectrum of BC progression, from in situ lesions to metastatic disease. Pathological evaluation revealed two distinct tumor morphologies, flat and nodular, which were largely determined by the mode of transplantation and intrinsic properties of the cell lines. Transcriptomic profiling implicated the TGF-β signaling pathway as a key regulator of this morphological divergence. Functional validation showed that SMAD4 knockout suppressed nodular growth, while constitutive activation of TGFBR1 enhanced tumor aggressiveness. Overall, this work identifies TGF-β signaling as a central driver of BC morphology and progression, and provides a robust and versatile resource of CDX models to support mechanistic and translational BC research.