bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–04–19
24 papers selected by
Xiao Qin, University of Oxford
  1. Mapping convergent regulators of melanoma drug resistance by PerturbFate.
  2. Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
  3. Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
  4. A mechanism for adaptive genome regulation in cancer.
  5. PACells identifies phenotype-associated cell states from single-cell chromatin accessibility profiles.
  6. Tackling the complexity of cancer with generative models.
  7. Cancer ecosystems: A dynamic interplay across scales.
  8. Hallmarks of Cancer: How did it inspire you?
  9. Mapping intratumor heterogeneity across layers for advancing immunotherapy.
  10. Cross-species single-cell and spatial transcriptomic mapping reveals EFNA1-EPHA4-mediated stem-like epithelial-macrophage crosstalk driving colorectal cancer progression.
  11. Toward AI-Powered Cancer Etiology Research.
  12. Dedifferentiation-driven oncogenic stemness promotes tumor-sustaining adaptability in the intestinal epithelium.
  13. Mechanical memory primes cells for confined migration.
  14. Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers.
  15. Cell death in cancer.
  16. The Hallmarks of Cancer: 25 years guiding discovery and therapy.
  17. Stromal biomarker-based framework for identifying pMMR/MSS and dMMR/MSI colorectal cancers with poor outcomes and limited benefit from immunotherapy.
  18. Hallmarks of cancer research: Enabling transformative discovery through global team science.
  19. Post-inflammatory polyps and risk of dysplasia in inflammatory bowel disease: Wolves in sheep's clothing?
  20. Early-onset colorectal cancer: rising rates require rising awareness.
  21. Microbiota and immune-related adverse events in cancer immunotherapy.
  22. Metastatic Odyssey: Decoding the Genomic Journey from Primary Colorectal Cancer to Disseminated Disease.
  23. The good, the bad, and the ugly: opportunities, challenges, and pitfalls in spatial proteomics modeling.
  24. Tumour promotion through the lens of evolution.
  1. Nature. 2026 Apr 15.
    Mapping convergent regulators of melanoma drug resistance by PerturbFate.
    Zihan Xu, Ziyu Lu, Aileen Ugurbil, Abdulraouf Abdulraouf, Andrew Liao, Jianxiang Zhang, Wei Zhou, Junyue Cao.
      High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.
    DOI:  https://doi.org/10.1038/s41586-026-10367-0
  2. Nature. 2026 Apr 15.
    Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
    Julian R Buissant des Amorie, Joris H Hageman, Sascha R Brunner, Suzanne E M van der Horst, Maria C Puschhof, Arne van Hoeck, Inge van Lierop, Sjors Middelkamp, Lisa van der Schee, Sven van Kempen, Folkert Morsink, Robin Geene, Sander Mertens, David S Cavigelli, Ingrid Verlaan-Klink, Lianne J Kraaier, Jorieke Salij, Renate Bezemer, Onno Kranenburg, Miangela M Laclé, Leon M G Moons, Hugo J G Snippert.
      Metastasis formation is classically considered a late-stage event in colorectal cancer evolution. Yet the time and spatial patterning by which metastatic competence is acquired remain poorly understood1,2. Here we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of colorectal cancer, concurrent with invasive front formation. However, although necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting extra bottlenecks such as immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumour progression stages within individual early-stage colorectal cancers. Whole-genome sequencing and growth factor-dependency assays exclude tumour cell-intrinsic acquired traits. By contrast, single-cell spatial atlases of the tumour microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid cocultures confirm that these trophocyte-like cancer-associated fibroblasts induce plastic transitioning to oncofetal states. Thus, interactions between tumour and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during colorectal cancer progression.
    DOI:  https://doi.org/10.1038/s41586-026-10344-7
  3. Cell. 2026 Apr 15. pii: S0092-8674(26)00333-8. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Jin Park, Philipp Weiler, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masilionis, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
    Keywords:  KRAS inhibitors; benign-to-malignant transition; niche dynamics; p53; pancreatic cancer; single-cell biology; spatial transcriptomics; tumor initiation; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.03.032
  4. Nature. 2026 04;652(8110): 581-590
    A mechanism for adaptive genome regulation in cancer.
    Gustavo S França, Itai Yanai.
      The ability of cancer cells to consistently escape therapy highlights their remarkable adaptive potential. A longstanding debate in cancer research concerns whether drug resistance originates primarily from mutational processes or through cellular plasticity. Emerging evidence has suggested that adaptive cellular states arise through phenotypic plasticity triggered by intracellular stress signals. Here we propose a theoretical framework for how such cellular adaptation in cancer drug resistance could be 'learned' by the AP-1 family of transcription factors. We highlight key AP-1 properties, including regulatory combinatorics, stress-induced feedback and cellular memory, and argue that this system constitutes a molecular framework for establishing drug-resistant cellular states. Finally, we discuss the potentially broad relevance of this adaptation mechanism beyond cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10269-1
  5. Am J Hum Genet. 2026 Apr 10. pii: S0002-9297(26)00122-9. [Epub ahead of print]
    PACells identifies phenotype-associated cell states from single-cell chromatin accessibility profiles.
    Jiao Hua, Qiongyu Sheng, Shutong Xiao, Yang Zhou, Jing Qi, Shuilin Jin.
      Identifying cell states that drive clinical phenotypes is crucial for dissecting regulatory landscapes, pathogenesis, and targeted therapies of disease in single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq). Here, we present PACells, a framework that links clinical phenotypes from bulk ATAC-seq data with individual cells from scATAC-seq data to identify critical cell states at single-cell resolution. PACells outperforms other methods in predicting cells and molecular signatures associated with disease and gene mutation. PACells discerns clinical cell states and regulatory elements relevant to Alzheimer disease (AD) and poor survival in glioblastoma. Further, PACells is extended to transcriptomics for melanoma datasets with immunotherapy outcomes.
    Keywords:  cell states; chromatin accessibility; clinical phenotypes; data integration
    DOI:  https://doi.org/10.1016/j.ajhg.2026.03.012
  6. Cell. 2026 Apr 16. pii: S0092-8674(26)00328-4. [Epub ahead of print]189(8): 2218-2231
    Tackling the complexity of cancer with generative models.
    Ashley Mae Conard, Madeline Hughes, James Hall, Neil Tenenholtz, Eric Zimmermann, Lorin Crawford, Ava P Amini, Kristen Severson.
      The Hallmarks of Cancer framework has played a seminal role in developing our understanding of cancer biology. By design, these hallmarks abstract cancer into a common set of functional capabilities. The hallmarks thus constitute an intentionally reductionist framework that has unified diverse observations and yielded valuable mechanistic insight, while leaving unresolved how these processes interact across scales. Complementary tools are therefore needed to capture cancer's inherently complex, multimodal, and multiscale nature. Here, we posit that generative models, built on the recent advances of artificial intelligence, are the key technology to capture this complexity and to thereby improve how we diagnose, understand, and intervene in cancer. Specifically, because of their ability to recognize complex patterns, process unstructured inputs, and synthesize multimodal inputs, generative models are poised to usher in a new era of biological discovery and clinical care. Ultimately, we envision a synergistic cycle wherein generative models of cancer and the Hallmarks of Cancer complement one another, the former driving hypothesis generation and discovery and the latter guiding the prioritization and development of new measurement tools.
    Keywords:  Hallmarks of Cancer; artificial intelligence; generative models; multimodal learning
    DOI:  https://doi.org/10.1016/j.cell.2026.03.027
  7. Cell. 2026 Apr 16. pii: S0092-8674(26)00270-9. [Epub ahead of print]189(8): 2441-2463
    Cancer ecosystems: A dynamic interplay across scales.
    Daniela F Quail, Johanna A Joyce.
      Tumors evolve within complex, adaptive ecosystems that operate across spatial, temporal, and systemic scales. Within each tumor microenvironment, numerous diverse cell populations assemble into specialized niches that are continually shaped by systemic physiology, environmental inputs, and therapeutic pressure. Beyond the local microenvironment, cancer progression is governed by the host macroenvironment, where intrinsic biological determinants intersect with modifiable factors to collectively impact physiological fitness and tissue resilience. Here, we propose a multi-scale framework that unites tumor biology with organismal physiology and reframes therapy from eliminating malignant cells in isolation to reprogramming the cellular, vascular, and systemic networks that sustain disease. We highlight emerging approaches that aim to restore physiological equilibrium, spanning from spatial multi-omics and AI-driven pathology to immune-vascular normalization and physiological conditioning. Together, these dimensions define an integrative vision for precision oncology that bridges discovery and intervention to achieve durable and ultimately curative cancer therapy.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.003
  8. Cell. 2026 Apr 16. pii: S0092-8674(26)00324-7. [Epub ahead of print]189(8): 2203-2205
    Hallmarks of Cancer: How did it inspire you?
    Lucas T Jae, Lillian L Siu, Lei Zhang, Anwesha Dey, Lisa M Coussens, Gerard Evan.
      In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the framework continues to guide discovery, encourage collaboration across disciplines, and inspire new ways to better understand and treat cancer.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.023
  9. Cell. 2026 Apr 16. pii: S0092-8674(26)00326-0. [Epub ahead of print]189(8): 2416-2440
    Mapping intratumor heterogeneity across layers for advancing immunotherapy.
    Jean-Christophe Marine, Osnat Bartok, Shira Sagie, Pietro Paolo Vitiello, Alberto Bardelli, Chen Weller, Tian-Gen Chang, Claudia Tonelli, Stefani Spranger, Eytan Ruppin, Yardena Samuels.
      Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and plasticity generate dynamic cancer cell states with distinct immune visibility. These layers of complexity converge on the immunopeptidome, the repertoire of peptides displayed by major histocompatibility complex molecules through which tumor cells are surveyed by T cells. Variation in antigen processing, presentation, and peptide abundance across cancer clones and cell states yields spatially and temporally distinct immunological niches that shape immune recognition and therapeutic response. Here, we summarize how multidimensional ITH manifests across cancer types and constrains immunotherapy efficacy. We propose that integrating measurements across layers is a promising direction for improving biomarker identification and informing more precise immune-based treatment strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.025
  10. Cancer Lett. 2026 Apr 09. pii: S0304-3835(26)00258-2. [Epub ahead of print]649 218495
    Cross-species single-cell and spatial transcriptomic mapping reveals EFNA1-EPHA4-mediated stem-like epithelial-macrophage crosstalk driving colorectal cancer progression.
    Siwen Zhang, Kun Xu, Yanyun Du, Zhenhao Liu, Hong Li, Bing Li, Lu Xie, Yunshi Zhong.
      Colorectal cancer (CRC) typically follows the "normal-adenoma-carcinoma" (NAC) progression, with approximately 70-90% of cases driven by an adenomatous polyposis coli (APC) mutation-dependent pathway. The Apc-mutant (Min) mouse, valuable for dissecting gene function and mechanisms in CRC, provides an important basis for cross-species analyses with human data. Here, we performed a cross-species analysis of single-cell and spatial transcriptomic data across multiple stages of colorectal tissues in both humans and Min mice, constructing a spatiotemporal atlas. Our study identified key microenvironmental regulatory networks involved in CRC progression and highlighted the central role of epithelial-macrophage interactions within the tumor microenvironment. We further validated the suitability of the Min mouse as a model for the intrinsic Consensus Molecular Subtypes 2(iCMS2) microsatellite-stable (MSS) subtype of CRC. Focusing on the crosstalk between tumor-associated macrophages (TAMs) and epithelial cells, we identified the EFNA1-EPHA4 axis as a critical regulator promoting the immunosuppressive polarization of TAMs and enhancing tumor cell stemness. In addition, inhibition of EFNA1 was found to slow tumor growth. This study not only provides a systematic framework for mapping CRC correspondence between humans and mice, but also uncovers key molecular mechanisms underlying CRC progression and proposes promising therapeutic targets.
    Keywords:  Colorectal cancer; Cross-species analysis; EFNA1-EPHA4; Single-cell transcriptomics; Spatial transcriptome analysis
    DOI:  https://doi.org/10.1016/j.canlet.2026.218495
  11. Cancer Discov. 2026 Apr 13. OF1-OF6
    Toward AI-Powered Cancer Etiology Research.
    Mengmeng Ji, Linying Zhang, Marinka Zitnik, George Hripcsak, Jason D Buenrostro, Yin Cao.
      Advances in multimodal longitudinal data and artificial intelligence (AI) create new opportunities for cancer etiology research. We envision an AI-powered discovery workflow integrating an interoperable epidemiologic data ecosystem and causal inference frameworks to accelerate the identification of both cancer causes and the converging biological states for prevention.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2098
  12. Cell Death Dis. 2026 Apr 17.
    Dedifferentiation-driven oncogenic stemness promotes tumor-sustaining adaptability in the intestinal epithelium.
    Kylee Zgeib, Thompson Hui, Simon Garcia, Zahra Hashemi, Shima Nejati, Amartya Singh, Atharva Inamdar, Crystal Lim, Dahlia Matouba, Christina Li, Binfeng Lu, Ansu O Perekatt.
      Intestinal tumorigenesis can occur via two distinct routes: bottom-up tumorigenesis occurs from mutations sustained in the Lgr5⁺ stem cells, whereas top-down tumorigenesis is driven by dedifferentiation of epithelial cells near the intestinal lumen. While sporadic human colon adenomas exhibit features of top-down tumorigenesis, their biological determinants remain elusive. Here, using a Smad4 loss-of-function and β-catenin gain-of-function (Smad4LOF:β-cateninGOF) mouse model, we demonstrate that dedifferentiation-derived oncogenic stem cells sustain tumorigenesis more effectively than endogenous mutant stem cells harboring the mutation. The dedifferentiating villi epithelial cells showed early expression of CD44 and Lgr5, supporting oncogenic stemness. Aberrant Notch signaling in the villi epithelium was also detected at the onset of dedifferentiation, suggesting its contribution to dedifferentiation. Single-cell RNA sequencing revealed a distinct population of dedifferentiation-derived stem cells enriched for proliferative, metabolic, and mouse embryonic stem cell-like gene signatures, consistent with enhanced plasticity and tumorigenic potential. These mutant cells exhibited growth factor independence, indicating a capacity for niche-independent proliferation and metabolic adaptation to sustain tumor growth. These findings identify dedifferentiation-driven stemness, aberrant Notch activation, and metabolic plasticity as cooperative mechanisms that promote top-down intestinal tumorigenesis. This study provides insight into how oncogenic dedifferentiation contributes to tumor heterogeneity and persistence and has implications for therapeutic resistance in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41419-026-08669-2
  13. Cell Rep. 2026 Apr 16. pii: S2211-1247(26)00345-1. [Epub ahead of print]45(4): 117267
    Mechanical memory primes cells for confined migration.
    Jia Wen Nicole Lee, Yeji Chang, Malhar S Chitnis, Yixuan Li, Xu Gao, Avery Rui Sun, Jin Zhu, Jennifer L Young, Andrew W Holle.
      When migratory cells move between stiffness niches in vivo, they encounter confined spaces imposed by extracellular matrix (ECM) networks. Cells from one niche possess mechanosensitive adaptations that influence their response to new environments, a concept known as mechanical memory. How this memory is acquired and how it influences migratory potential in confinement remain poorly understood. Here, we combine stiffness priming using polyacrylamide hydrogels with a confinement platform to screen memory across healthy and transformed cells. Using a dose-and-passage approach, we find that cells primed on soft substrates navigate confinement more efficiently. Bulk RNA sequencing identifies NFATC2 as a transcription factor mediating mechanical memory through genetic reprogramming. Inhibition of NFATC2 confirms that it is required for memory acquisition and enhanced confined migration. Highly invasive cancer cells fail to retain mechanically induced phenotypes following cue removal, suggesting differential adaptation strategies. These findings establish mechanical memory as a cell-intrinsic regulator of confined migration.
    Keywords:  CP: cell biology; NFATC2; cell migration; confined migration; mechanical memory; mechanotransduction; substrate stiffness; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117267
  14. Cell. 2026 Apr 16. pii: S0092-8674(26)00286-2. [Epub ahead of print]189(8): 2232-2253
    Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers.
    Mengyao Shi, Gary J Patti, Marc J Gunter, Ramaswamy Govindan, Iris Lansdorp-Vogelaar, Ting Wang, Jeffrey P Townsend, Graham A Colditz, Yasmine Belkaid, Yin Cao.
      Cancer in younger adults is rising globally, with notable birth-cohort effects. This epidemiological shift underscores the urgent need to accelerate the identification of novel causes and underlying biological networks, with the aim of translating these insights into prevention and interception strategies. In this perspective, we revisit the major milestones in the discovery of cancer causes and outline challenges that hinder progress. To address these challenges, we advocate closer integration of epidemiologic and mechanistic studies and propose three interconnected frameworks that extend current epidemiologic approaches: a tissue ecosystem-anchored framework for cancer cause discovery, a biological state-based framework for precision cancer risk assessment, and a dynamic framework to characterize cancer preventability. This roadmap aims to stimulate conceptual, resource, and methodological advances to accelerate cancer etiology research and prevention in the era of rising early-onset cancers.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.019
  15. Cell. 2026 Apr 16. pii: S0092-8674(26)00325-9. [Epub ahead of print]189(8): 2322-2356
    Cell death in cancer.
    Marcus Conrad, Andreas Strasser, Philipp J Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida.
      "Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.024
  16. Cell. 2026 Apr 16. pii: S0092-8674(26)00334-X. [Epub ahead of print]189(8): 2195-2196
    The Hallmarks of Cancer: 25 years guiding discovery and therapy.
    Cell Editorial Team
      Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding of cancer, guided drug development, and evolved to incorporate new discoveries and address emerging challenges.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.033
  17. Gut. 2026 Apr 14. pii: gutjnl-2025-336804. [Epub ahead of print]
    Stromal biomarker-based framework for identifying pMMR/MSS and dMMR/MSI colorectal cancers with poor outcomes and limited benefit from immunotherapy.
    Mar Iglesias Coma, Jordi Badia-Ramentol, Carolina Martinez-Ciarpaglini, Jenniffer Linares, Noelia Tarazona, Nuria Mulet-Margalef, Paula Tornero-Piñero, Anna Sallent-Aragay, Alba Recort-Bascuas, Joan Gibert, Marta Sant-Albors, Daniele V F Tauriello, Melba Cruz-Moral, Marina Carreras-Gallardo, Elena Sancho, Clara Morral Martinez, Marta Garrido, Jose Luis Manzano Mozo, Andrés Cervantes, Clara Montagut, Eduard Batlle, Alexandre Calon.
       BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, with clinical progress limited by intratumoural cellular diversity and the absence of robust, informative markers.
    OBJECTIVE: Leveraging the heterogeneity of cancer-associated fibroblasts (CAFs) within the tumour microenvironment, this study aims to identify and evaluate candidate biomarkers to support patient stratification and improve prediction of therapeutic responses.
    DESIGN: We applied a multiomic approach integrating single-cell RNA sequencing, computational cell deconvolution and protein-level assessment from patient tumours, complemented by in vitro and in vivo preclinical models, to characterise stromal populations linked to CRC progression and treatment resistance.
    RESULTS: Retrospective analysis of over 3000 patient samples across multiple cohorts identified a distinct subset of CAFs expressing collagen triple helix repeat containing 1 (CTHRC1). CTHRC1(+) CAFs were associated with increased transforming growth factor-beta (TGF-beta) signalling and poor clinical outcomes in early and advanced disease stages. CTHRC1(+) CAFs enabled stratification of both mismatch repair-deficient/microsatellite instability (dMMR/MSI) and mismatch repair-proficient/microsatellite stability (pMMR/MSS) tumours into immune-inflamed and poorly immunogenic subtypes. Retrospective analysis of several clinical trials revealed that CTHRC1(+) CAFs are linked to resistance to immune checkpoint inhibitors in MSI and MSS tumours, suggesting therapeutic potential for combining TGF-beta blockade with immunotherapy.
    CONCLUSION: CTHRC1-expressing CAFs represent clinically relevant biomarkers that link molecular profiling with diagnostic pathology. Our findings support the potential incorporation of CTHRC1(+) CAF assessment into routine histopathological workflows, pending prospective validation, and suggest a framework for stroma-informed CRC stratification, particularly in patients with stroma-rich, treatment-resistant tumours and pMMR/MSS with limited therapeutic options.
    Keywords:  BIOMARKERS; COLORECTAL CANCER; IMMUNOHISTOPATHOLOGY; MYOFIBROBLASTS
    DOI:  https://doi.org/10.1136/gutjnl-2025-336804
  18. Cell. 2026 Apr 16. pii: S0092-8674(26)00323-5. [Epub ahead of print]189(8): 2209-2213
    Hallmarks of cancer research: Enabling transformative discovery through global team science.
    Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Andrew Kurtz, Dinah S Singer, David Scott.
      Since the original Hallmarks of Cancer, our understanding of the complexity of the disease has expanded dramatically. Researching cancer is no longer simply a question of ever more sophisticated experiments but of delivering science in an evolving and complex system. Here, we discuss how to support global team science and catalyze transformative discovery, drawing on our experience from the Cancer Grand Challenges initiative.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.022
  19. Endosc Int Open. 2026 ;14 a28189346
    Post-inflammatory polyps and risk of dysplasia in inflammatory bowel disease: Wolves in sheep's clothing?
    Elena De Cristofaro, Antonio Fonsi, Giovanni Monteleone, Irene Marafini.
      Patients with longstanding and extensive inflammatory bowel disease (IBD) have an enhanced risk of colorectal cancer (CRC), which accounts for up to 10% of all IBD-related deaths. Chronicity of bowel inflammation, co-existence of primary sclerosing cholangitis, and a family history of sporadic colorectal cancer represent further risk factors for development of CRC. Colon post-inflammatory polyps are believed to be another risk factor for IBD-associated CRC, even though it remains unclear how presence of such lesions could influence CRC development. Although earlier observational studies suggested an association between post-inflammatory polyps and colorectal neoplasia, more recent studies have indicated that these lesions do not independently increase neoplasia risk. However, they may, nonetheless, complicate surveillance by obscuring dysplastic lesions, particularly when numerous, and they are best regarded as markers of chronic and recurrent mucosal inflammation. Moreover, emerging evidence suggests that a minority of post-inflammatory-like lesions may conceal or coexist with dysplasia, underscoring the diagnostic challenge posed by polypoid lesions in chronically inflamed mucosa. In this article, we review the available data about the association between post-inflammatory polyps and development of CRC in IBD and discuss how advances in technology, particularly development of artificial intelligence models integrated with endoscopy, may contribute to their appropriate management.
    Keywords:  Colorectal cancer; Endoscopy Lower GI Tract; Inflammatory bowel disease; Polyps / adenomas / ...
    DOI:  https://doi.org/10.1055/a-2818-9346
  20. Lancet Gastroenterol Hepatol. 2026 May;pii: S2468-1253(26)00096-8. [Epub ahead of print]11(5): 345
    Early-onset colorectal cancer: rising rates require rising awareness.
    The Lancet Gastroenterology Hepatology.
      
    DOI:  https://doi.org/10.1016/S2468-1253(26)00096-8
  21. Nat Rev Cancer. 2026 Apr 16.
    Microbiota and immune-related adverse events in cancer immunotherapy.
    Sarah M Schneider, Christopher Fan, Yinghong Wang, Robert R Jenq, Stephanie S Watowich.
      In response to treatment with immune checkpoint inhibitors (ICIs), patients with cancer can develop immune-related adverse events (irAEs), which are off-target toxicities affecting non-tumour tissues. Development of an irAE can require cessation of ICI treatment and cause additional morbidities, unrelated to cancer. Although the mechanisms that drive irAEs remain largely unknown, thus limiting treatment strategies, emerging evidence implicates tissue microbiomes, particularly in the gastrointestinal tract, lung and skin, as potential mediators. Here we review evidence that supports roles for the microbiome in irAEs. We focus on ICI colitis, a common irAE that has strong association with the gut microbiome. We examine clinical and preclinical studies that shed light on the immune and microbial drivers of ICI colitis and discuss current experimental treatments. By summarizing recent findings, we aim to encourage research into therapies that reduce irAE risk and severity while preserving anti-tumour efficacy of ICI treatment.
    DOI:  https://doi.org/10.1038/s41568-026-00921-3
  22. Cancers (Basel). 2026 Mar 25. pii: 1062. [Epub ahead of print]18(7):
    Metastatic Odyssey: Decoding the Genomic Journey from Primary Colorectal Cancer to Disseminated Disease.
    Taxiarchis Konstantinos Nikolouzakis, John Souglakos, Epameinondas Evangelos Kantidakis, Katerina Achilleos, Troye van Staden, Emmanuel Chrysos.
      Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early-before clinical detection-challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories-from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity-with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition.
    Keywords:  circulating tumor DNA; colorectal cancer; genomics; metastasis; organotropism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18071062
  23. Brief Bioinform. 2026 Mar 01. pii: bbag169. [Epub ahead of print]27(2):
    The good, the bad, and the ugly: opportunities, challenges, and pitfalls in spatial proteomics modeling.
    Shahil Yasar Haque, Swakkhar Shatabda, Salekul Islam, Shoaib Ahmed Dipu, Riasat Azim.
      Spatial proteomics has become one of the mainstays of spatial biology at an impressive speed. It enables the in-depth study of protein abundance, localization, and microenvironmental context at the levels of tissues, cells, and subcellular structures. Preserving the native tissue architecture and capturing the functional molecular states that cannot be deduced from transcriptomics, spatial proteomics is breaking new grounds in cellular heterogeneity, small-unit physiological niches, and disease-related tissue organization. This review covers the major strengths ("Good") of the field, including mass spectrometry imaging, single-cell, and subcellular proteomics, by which these technological advancements in protein biology mapping at different scales have been merged. This review also discussed the limitations and trade-offs ("Bad") that consist of issues that cause throughput bottlenecks, sensitivity constraints, antibody specificity problems, and multi-omics integration challenges. Afterwards, this review also points out the pitfalls ("Ugly") that can result in misguided research judgments associated with false spatial gradients, protein delocalization, segmentation artifacts, batch effects, and improperly validated spatial maps. Finally, the review discusses the future research directions that can lead spatial proteomics towards greater advancement, which will lead to revolutionary improvements in biological mechanisms, translational research, and precision medicine.
    Keywords:  cellular heterogeneity; multi-omics; protein localization; spatial proteomics
    DOI:  https://doi.org/10.1093/bib/bbag169
  24. Nature. 2026 04;652(8110): 591-601
    Tumour promotion through the lens of evolution.
    Nuria Lopez-Bigas, Eve Kandyba, Abel Gonzalez-Perez, Paul Brennan, Allan Balmain.
      Almost all tumours carry one or more cancer driver mutations, which are essential for cell transformation. However, recent advances in cancer genomics have demonstrated that normal human tissues contain millions of cells carrying known driver mutations, while preserving homeostasis. Most of these mutated cells will never transform into tumours. Moreover, studies of known or suspected human carcinogens have shown that the majority are not mutagens. These observations suggest that exogenous carcinogenic exposures might increase cancer risk by modifying selective constraints, promoting the expansion of pre-existing clones carrying specific oncogenic mutations. In this Review, we propose a synthesis between ideas put forward almost a century ago based on seminal experiments on carcinogen-induced tumours in mice, observations made by cancer epidemiologists over several decades, and the recent revelation that normal human tissues are a patchwork of mutant clones. The repeated interplay between variation and selection-the first principles of Darwinian evolution-underlies the clonal selection leading to tumorigenesis. A deeper understanding of these processes can enhance prospects for cancer prevention by eliminating or mitigating the effects of environmental or endogenous tumour promoters.
    DOI:  https://doi.org/10.1038/s41586-026-10386-x
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