bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–04–26
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
  2. Maladaptive Inflammatory Signaling in Old Mice Impairs Colonic Regeneration by Promoting a Sustained Fetal-Like Epithelial State.
  3. Low inflammation correlates with protumor Tim4+TREM1+ resident macrophage expansion and limited monocyte-derived macrophage differentiation during peritoneal colorectal cancer.
  4. SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.
  5. Ferroptosis surveillance: Insights from in vivo contexts.
  6. Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
  7. TGF-β/SMAD4/14-3-3σ/TFEB axis promotes mesenchymal-epithelial transition and inhibits autophagy in colorectal cancer.
  8. Morphological control of gut lumen access shapes enteroendoceine cell function.
  9. A cell-death protein has an unexpected role in intestinal repair.
  10. Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling.
  11. Epigenetic reprogramming of hexokinase domain containing 1 (HKDC1) promotes proliferation in colorectal cancer.
  12. Early fibrotic niches establish tumour-permissive microenvironments.
  13. Mechanical load inhibits cancer growth in mouse and human hearts.
  14. Cancer signaling beyond the genes.
  15. Molecular lineages of sporadic mismatch-repair deficient colorectal cancer.
  16. Gut microbiota-driven pre-metastatic niche formation in colorectal cancer liver metastasis: mechanisms and translational significance.
  17. The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
  18. Epigenetic fingerprints link early-onset colon and rectal cancer to pesticide exposure.
  1. FEBS J. 2026 Apr 24.
    Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
    Abdulsamie Hanano, Amal Yousfan.
      Fatty acids (FAs) are essential for cellular growth and homeostasis; however, their excessive accumulation induces lipotoxicity. To prevent FA-induced damage, eukaryotic cells sequester surplus FAs within cytosolic lipid droplets (LDs), dynamic organelles central to lipid storage, metabolism, and signaling. Emerging evidence indicates that LDs suppress ferroptosis, an iron-dependent programmed cell death, by channeling polyunsaturated fatty acids (PUFAs) away from membrane phospholipids, thereby limiting lipid peroxidation. Nonetheless, the molecular mechanisms linking LD biogenesis to ferroptosis susceptibility remain poorly defined. In a recent study published in The FEBS Journal, Kump et al., provided mechanistic insights into how triacylglycerol (TGs) biosynthesis and LD assembly regulate ferroptosis in cancer cells as a function of PUFA availability. Here, we discuss and contextualize their principal findings.
    Keywords:  Acyl‐CoA diacylglycerol acyltransferase; ferroptosis; lipid droplets; lipid peroxidation; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1111/febs.70567
  2. Aging Cell. 2026 May;25(5): e70495
    Maladaptive Inflammatory Signaling in Old Mice Impairs Colonic Regeneration by Promoting a Sustained Fetal-Like Epithelial State.
    Antonion Korcari, Helen Tauc, Jeff Duggan, Jina Yun, Fabien Wehbe, Spyros Darmanis, Zora Modrusan, Rajita Pappu, David Garfield, Heinrich Jasper, David Castillo-Azofeifa.
      Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized, among other changes, by the induction of an interferon γ (IFNγ) response signature in immune cells. This does not result in increased inflammatory signatures in the epithelium under homeostasis but triggers a disproportionate inflammatory response that disrupts regeneration and epithelial integrity after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFNγ by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5+ stem cells and decreased epithelial proliferation. Interestingly, we find that aged intestinal epithelial cells express an elevated regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFNγ-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.
    Keywords:  IFNγ; aging; fetal‐like reversion; inflammaging; inflammation; intestine; regeneration; regenerative medicine
    DOI:  https://doi.org/10.1111/acel.70495
  3. Cancer Immunol Res. 2026 Apr 23.
    Low inflammation correlates with protumor Tim4+TREM1+ resident macrophage expansion and limited monocyte-derived macrophage differentiation during peritoneal colorectal cancer.
    Margarita Ferriz, Natalia Alvarez-Ladrón, Alejandra Gutiérrez-González, Marta H Fernández-Sesma, Adrián Vega-Pérez, Juan Carlos Oliveros, Ana Cayuela López, Eduard Batlle, Daniele V Tauriello, Alejandro Prados, Carlos Ardavín.
      Accumulating evidence indicates that peritoneal macrophages, comprising resident peritoneal macrophages (resMØs) and monocyte-derived non-resident macrophages (moMØs), contribute to peritoneal tumor progression, by promoting tumor cell proliferation and migration, and driving immunosuppression. However, the mechanisms governing the expansion of resMØs and moMØs, as well as their differential contributions to the peritoneal macrophage pool in tumor‑bearing mice and to tumor growth, remain to be elucidated. Using a mouse model of colorectal cancer (CRC) peritoneal metastasis, induced by intraperitoneal injection of tumor organoids derived from primary tumors in genetically engineered mice carrying Apc, Kras, Tgfbr2, and Trp53 mutations, and recapitulating human‑like metastatic CRC, we investigated the origin, expansion, and function of peritoneal macrophages during metastatic tumor growth. Our data support that the low inflammatory status of the peritoneal cavity during CRC peritoneal tumor growth restrains monocyte recruitment and the formation of Tim4⁻ resMØs and moMØs, while enabling a marked, proliferation‑driven expansion of Tim4⁺ resMØs. Tumor‑induced Tim4⁺ resMØs displayed a migratory and protumor transcriptomic signature, characterized by the activation of genes encoding key pro‑tumorigenic molecules and potential immunotherapeutic targets, including A2A/A2B, ARG1, IDO, IRG1, MMP12, PD-L1/2, SPP1, TREM1 or VEGF. Correspondingly, during peritoneal CRC tumor growth, Tim4⁺ TREM1⁺ resMØs migrated to the omentum, the principal peritoneal target organ for metastasis, and promoted CRC peritoneal tumor progression. These findings may contribute to the development of immunotherapies for CRC peritoneal metastasis that target tumor‑associated peritoneal macrophages.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0388
  4. Free Radic Biol Med. 2026 Apr 20. pii: S0891-5849(26)00427-2. [Epub ahead of print]
    SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.
    Zhen Wang, Jinghu He, E Jifu, Ying Yang, Xiaohong Yang.
      Accumulating evidence indicates that mitochondrial dysfunction is a hallmark of cancer. Nonetheless, the mechanisms linking mitochondrial dysfunction to cancer progression remain largely elusive. SLC25A48 was recently recognized as a transporter involved in mitochondrial choline uptake. Nevertheless, the roles of SLC25A48 in human malignancies remain unexplored. Here, we found that SLC25A48 is elevated in colorectal cancer (CRC) tissues and associates with unfavorable patient outcomes. Functional analyses showed that SLC25A48 accelerates the growth of CRC by enhancing proliferative capacity and preventing cell death. Mechanistically, SLC25A48 exerts its oncogenic function by enhancing the synthesis of choline-derived betaine, which is an important source of one-carbon units for numerous biosynthetic processes. On the one hand, SLC25A48 mitigates oxidative stress-induced ferroptosis by augmenting NADPH availability. On the other hand, it enhances cell proliferation by promoting mitochondrial energy production through upregulating mitochondrial DNA (mtDNA) replication and transcription. Importantly, silencing of SLC25A48 augmented the responsiveness of CRC cells to RSL3-induced ferroptosis and 5-FU-based chemotherapy. Furthermore, increased CTCF expression may contribute, at least in part, to the upregulation of SLC25A48 in CRC. Collectively, our data emphasize that SLC25A48 plays a critical oncogenic role in CRC and holds potential as a druggable target to overcome drug resistance in CRC.
    Keywords:  SLC25A48; chemotherapy resistance; colorectal cancer; ferroptosis; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.136
  5. Ferroptosis Oxid Stress. 2026 ;pii: 202523. [Epub ahead of print]2(3):
    Ferroptosis surveillance: Insights from in vivo contexts.
    Alec J Vaughan, Mario Palma, Jessalyn M Ubellacker, Thales Papagiannakopoulos.
      Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.
    Keywords:  Ferroptosis; GPX4–FSP1 axis; in vivo modeling; microenvironment
    DOI:  https://doi.org/10.70401/fos.2026.0021
  6. Nature. 2026 Apr 22.
    Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
    JRI Live Cell Bank
      Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41586-026-10343-8
  7. Cell Death Dis. 2026 Apr 21. pii: 397. [Epub ahead of print]17(1):
    TGF-β/SMAD4/14-3-3σ/TFEB axis promotes mesenchymal-epithelial transition and inhibits autophagy in colorectal cancer.
    Xiaoyan Chen, Markus Winter, Matjaz Rokavec, Janine König, Heiko Hermeking.
      14-3-3σ is a p53-inducible gene with tumor suppressive properties and SMAD4 is a transcription factor encoded by a tumor suppressor gene, which is commonly inactivated in colorectal cancer (CRC). Here, 14-3-3σ was characterized as direct transcriptional target of SMAD4. TGF-β treatment of tumoroids derived from CRC patients and mouse models resulted in a SMAD4-dependent induction of 14-3-3σ. In murine, intestinal epithelia, the apical expression of 14-3-3σ was dependent on Smad4. Ectopic SMAD4 or 14-3-3σ promoted mesenchymal-to-epithelial transition (MET) and suppressed invasion, migration, and autophagy of CRC cells. As experimental inactivation of 14-3-3σ abolished these tumor-suppressive functions of SMAD4, 14-3-3σ mediates these effects of SMAD4. Inhibition of autophagy and promotion of MET by SMAD4 was mediated by inhibition of TFEB via binding and sequestration of TFEB by 14-3-3σ. The association of 14-3-3σ and TFEB was dependent on phosphorylation of the TFEB serine 211 residue, which is a target of mTORC1. Taken together, the TGF-β/SMAD4/14-3-3σ/TFEB axes characterized here antagonizes epithelial plasticity and autophagy. Thereby, it may ultimately suppress the progression of CRC and other types of cancer.
    DOI:  https://doi.org/10.1038/s41419-026-08733-x
  8. J Cell Biol. 2026 May 04. pii: e202603173. [Epub ahead of print]225(5):
    Morphological control of gut lumen access shapes enteroendoceine cell function.
    Qingyin Qian, Ryusuke Niwa, Yu-Ichiro Nakajima.
      In this issue, Yu et al. (https://doi.org/10.1083/jcb.202506084) uncover a genetic mechanism that determines whether enteroendocrine cells access the gut lumen. Their findings link regional transcriptional control to epithelial integration of enteroendocrine cells, revealing how cell morphology shapes nutrient sensing in the intestinal epithelium.
    DOI:  https://doi.org/10.1083/jcb.202603173
  9. Nature. 2026 Apr;652(8112): 1135-1137
    A cell-death protein has an unexpected role in intestinal repair.
    Ayijiang Yisimayi, Judy Lieberman.
      
    Keywords:  Cell biology; Molecular biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-00810-7
  10. Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00186-2. [Epub ahead of print] 102769
    Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling.
    Jie Liu, Mei Li, Jianming Huang, Yujie Xia, Guanfeng Jiang, Hong'an Zhang, Jiaxin Yang, Mingfeng Jiang, Yalan Liu, Yilun Luo, Liefeng Wang, Shuyong Zhang.
      Targeted therapy for advanced colorectal cancer (CRC) remains a significant unmet clinical need. Here, we investigate the mechanism of the anti-TROP2 antibody-drug conjugate IMMU132, delivering SN-38 to induce TOP1-mediated DNA damage and cytotoxicity. We further discover that it concurrently suppresses the PERK-eIF2α-ATF4 axis of the unfolded protein response, a key adaptive survival pathway activated by therapy-induced endoplasmic reticulum (ER) stress. This dual action of direct killing and stress adaptation disruption may dismantle a key resistance mechanism. Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies.
    Keywords:  PERK; TROP2; antibody drug conjugate; colorectal cancer; endoplasmic reticulum stress; synergistic effect
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102769
  11. Am J Cancer Res. 2026 ;16(3): 1013-1026
    Epigenetic reprogramming of hexokinase domain containing 1 (HKDC1) promotes proliferation in colorectal cancer.
    Kuo-Hsing Chen, Liang-Chuan Lai, Liang-In Lin, Chia-Lang Hsu, Yi-Hsin Liang, Been-Ren Lin, Ann-Lii Cheng, Eric Y Chuang, Kun-Huei Yeh.
      Dysregulation of cellular metabolism is one of the hallmarks of cancer. Tumor cells would enhance glycolysis to fuel the phenotypes of rapid proliferation and invasion. This study aims to explore epigenetic reprogramming of glycolysis pathway in colorectal cancer (CRC). CRCs and the adjacent normal colon tissues were profiled by using a comprehensive methylation array (Illumina Methylation EPIC Beadchips) to comprehensively analyze the methylation alterations in the glycolysis pathway. Differentially methylated genes (DMGs) were identified by using β value difference (≥ 0.2 or ≤ -0.2) and Wilcoxon rank-sum test (P < 0.05), and the common DMG in open datasets (GSE42752, GSE25062 and TCGA). Pyrosequencing was executed to validate the DMGs. Hexokinase domain containing 1 (HKDC1), the major hypomethylated gene we found, was overexpressed in colon cancer cells. Cells were treated with an HKDC1 inhibitor to elucidate the role of HKDC1. We found hypomethylation of HKDC1 was the only shared hypomethylated DMG in glycolysis pathway after comparing our methylation profiles of CRC to 3 public datasets. The RT-qPCR study in our cohort and the negative association between mRNA expression of HKDC1 and methylation status in TCGA dataset support HDKC1 expression is methylation-regulated. Overexpression of HKDC1 in colon cancer cells resulted in increased proliferation of colon cancer cells and decreased cytotoxicity by an HKDC1 inhibitor. RNA sequencing revealed significant up-regulation of glycolysis, cell cycle, E2F, and its targets in HKDC1 overexpressed cells. In summary, hypomethylation of HKDC1 is common in CRC and may regulate cellular metabolism to promote proliferation of colon cancer cells through upregulation of glycolysis and cell cycle pathways.
    Keywords:  Colorectal cancer; HKDC1; cancer metabolism; cell cycle; epigenetics; glycolysis
    DOI:  https://doi.org/10.62347/OSSN5233
  12. Nature. 2026 Apr 22.
    Early fibrotic niches establish tumour-permissive microenvironments.
    Erik C Cardoso, Hyeyoung Lee, Frances J England, Hyunjin Cho, Robin Lu, Sagar S Varankar, Moo Suk Park, Natasha Rekhtman, Bon-Kyoung Koo, Benjamin D Simons, Jinwook Choi, Joo-Hyeon Lee.
      Pathologic transformation represents a critical yet poorly defined window during which mutant epithelial stem cells actively construct the microenvironment that enables tumour initiation1,2. Here using integrated single-cell, spatial and functional analyses, we define the earliest multicellular events that licence this transition following oncogenic activation in the lung. KrasG12D-mutant alveolar type II cells rapidly adopt regenerative-like states that act as signalling hubs, orchestrating coordinated stromal and immune reprogramming while enhancing epithelial plasticity. Through secretion of amphiregulin, mutant epithelial cells activate EGFR signalling in adjacent fibroblasts, inducing a fibrotic, injury-like programme. Reprogrammed fibroblasts, in turn, expand and reprogramme alveolar macrophages, amplifying inflammatory signalling and reinforcing epithelial plasticity. These reciprocal interactions establish a self-sustaining epithelial-stromal-immune circuit that generates a tumour-permissive niche before malignant outgrowth. Disruption of the amphiregulin-EGFR axis prevents early niche formation and abrogates tumour initiation. Conservation of this programme in KRASG12D-inducible human alveolar organoids and early-stage lung adenocarcinoma tissues identifies epithelial-microenvironment communication as a therapeutically actionable vulnerability and suggests that intercepting niche formation may prevent progression to treatment-resistant disease.
    DOI:  https://doi.org/10.1038/s41586-026-10399-6
  13. Science. 2026 Apr 23. 392(6796): eads9412
    Mechanical load inhibits cancer growth in mouse and human hearts.
    Giulio Ciucci, Daniela Lorizio, Nicoletta Bartoloni, Mauricio Budini, Andrea Colliva, Simone Vodret, Anh-Vu Nguyen, Lorenzo Ciacci, Bernhard Texler, Benno Cardini, Rupert Oberhuber, Sofia Bindelli, Ilaria Luciana Carlotta Del Giudice, Roman Vuerich, Francesco Riccitelli, Elena Zago, Henrik Nicolay Finsberg, Mattia Chiesa, Gianluca Lorenzo Perrucci, Rossana Bussani, Furio Silvestri, Manuel Maglione, Gaetano Ivan Dellino, Gianfranco Sinagra, Mauro Giacca, Thomas Eschenhagen, Paolo Golino, Giulio Pompilio, Pier Giuseppe Pelicci, Laura Andolfi, Maurizio Pinamonti, Matteo Dal Ferro, Samuel Wall, Francesco S Loffredo, Serena Zacchigna.
      The heart rarely develops cancer, and, at the same time, it lacks regenerative capacity, as cardiomyocytes stop proliferating after birth. This suggests that mechanisms limiting cardiac regeneration may also protect against cancer. In this work, we investigated the role of mechanical load and used in vivo cancer models and ex vivo engineered heart tissues to show that mechanical load reduces cancer cell proliferation in the myocardium. Spatial transcriptomics of human cardiac metastases revealed decreased histone methylation and chromatin compaction. These changes affect chromatin accessibility at proliferation-related loci, with Nesprin-2 identified as a key mechanosensor. Our results uncover how mechanical forces protect the heart from cancer and suggest potential strategies for cancer therapy based on mechanical stimulation.
    DOI:  https://doi.org/10.1126/science.ads9412
  14. Curr Opin Cell Biol. 2026 Apr 17. pii: S0955-0674(26)00031-1. [Epub ahead of print]100 102643
    Cancer signaling beyond the genes.
    Andre Levchenko, Ralitsa R Madsen.
      Cancer is still largely interpreted through the lens of genetic mutations, which continues to shape most therapeutic strategies. Yet single cell analyses reveal limits to this view: phenotypic heterogeneity is pervasive even among genetically identical cancer cells, and many canonical driver mutations are also present in non-malignant tissues. These paradoxes can be reconciled by viewing cancer as a new tissue state characterized by aberrant cellular information processing, where mutations act as context-dependent modifiers of the signaling codes. We advance a framework in which input-specific signaling dynamics determine phenotypic outcomes, while oncogenic mutations bias and blur these dynamics rather than acting as simple "on-off" switches. In this view, therapeutic success depends on restoring the fidelity of dynamic signal encoding and decoding rather than merely inhibiting isolated pathway components.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102643
  15. Clin Cancer Res. 2026 Apr 21.
    Molecular lineages of sporadic mismatch-repair deficient colorectal cancer.
    Michael B Foote, Guilherme Harada, Somer Abdelfattah, Nil Urganci, Paolo Manca, Jinru Shia, Henry Walch, Guillem Argilés, Oliver Artz, Rona Yaeger, Maliha Nusrat, Shrey Patel, Paul Johannet, Emily C Harrold, Benoit Rousseau, Zsofia Stadler, Callahan Wilde, Vetri Sudar Jayaprakasam, Chiara Cremolini, Sara Lonardi, Andrea Cercek, Leonard Saltz, Efsevia Vakiani, Filippo Pietrantonio, Yelena Janjigian, Nikolaus Schultz, Alexander Drilon, Luis A Diaz.
       PURPOSE: Mismatch-repair deficient (MMRd) colorectal cancers (CRC) are classified based on MMR protein loss and BRAF-V600E mutations. BRAF-wild-type(wt) sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biologic and clinical significance. We evaluated mutually-exclusive subtypes of sporadic MMRd tumors defined by oncogenic MAPK variants and gene fusions to determine the relationship between predominant genomic driver, MMR deficiency mechanism, and clinical outcomes.
    PATIENTS AND METHODS: We assessed 6,789 patients with CRC sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd CRC. We defined mutually-exclusive oncogenic alteration subtypes, then assessed differences in allele-specific MMR-inactivating events, co-occurring oncogenic variants, and patient outcomes. We validated findings in an Italian cohort (n=69).
    RESULTS: We identify four sporadic MMRd CRC subtypes: (i) oncogenic fusion-positive, (ii) RAS-mutant(mut), (iii) BRAF-V600E-mut, and (iv) MAPK/fusion driver-negative. These mutually-exclusive subtypes were associated with conserved molecular lineages of MMR gene inactivation and WNT signaling variants. Oncogenic fusions were disproportionately prevalent in non-Caucasians, non-smokers and in the transverse colon, compared to subtypes that were enriched in smokers (BRAF-mut) and male, younger patients (RAS-mut and MAPK/fusion-driverless). Oncogene-defined molecular lineages were strong predictors of patient outcomes and response to immunotherapy and tyrosine kinase inhibition for metastatic disease. Fusion-positive patients demonstrated improved survival compared to BRAF mutant cancers and benefitted from immunotherapy and fusion inhibitors. MAPK/fusion driver negative tumors were aneuploid, responded poorly to immunotherapy, and were sensitive to EGFR blockade.
    CONCLUSIONS: Overall, MAPK and fusion oncogenic drivers distinguish MMRd CRC molecular lineages that inform molecular and clinical phenotypes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-26-0024
  16. Gut Pathog. 2026 Apr 21.
    Gut microbiota-driven pre-metastatic niche formation in colorectal cancer liver metastasis: mechanisms and translational significance.
    Pengyu Chen, Qian Geng, Wenyu Zhu, Hua Jiang.
       BACKGROUND: Liver metastasis of colorectal cancer (CRC) remains a major clinical challenge, closely linked to poor prognosis and limited therapeutic efficacy. Emerging evidence implicates the gut microbiota in orchestrating the formation and maturation of the hepatic pre-metastatic niche (PMN) through the gut-liver axis.
    MAIN BODY: Dysbiosis-induced disruption of intestinal barrier integrity facilitates microbial translocation, which triggers hepatic inflammation, immune suppression, metabolic reprogramming, and vascular remodelling, together creating a permissive soil for metastatic seeding. Among pathogenic taxa, Fusobacterium nucleatum has emerged as a key driver because it persistently colonises both primary tumours and hepatic metastases while modulating immunotolerance and chemoresistance. Therapeutically, narrow-spectrum antimicrobial approaches that target pro-metastatic taxa show promise for safely and selectively correcting microbiota-mediated PMN formation. In addition, faecal microbiota transplantation (FMT) combined with immune checkpoint inhibitors and anti-angiogenic therapy has yielded encouraging responses in refractory metastatic CRC by boosting anti-tumour immunity and restoring hepatic microvascular architecture.
    CONCLUSION: Future research should integrate multidimensional biomarker assessment with personalised, microbiota-based therapeutic frameworks to achieve effective and durable prevention of CRC liver metastasis.
    Keywords:  Colorectal cancer; Gut microbiota; Gut-liver axis; Liver metastasis; Pre-metastatic niche
    DOI:  https://doi.org/10.1186/s13099-026-00832-6
  17. Nat Rev Cancer. 2026 Apr 24.
    The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
    Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo, Gregoire Lauvau, Maria Soledad Sosa.
      Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41568-026-00928-w
  18. Nat Med. 2026 Apr 21.
    Epigenetic fingerprints link early-onset colon and rectal cancer to pesticide exposure.
    Silvana C E Maas, Iosune Baraibar, Lea Lemler, Maria Butjosa-Espín, Odei Blanco Irazuegui, Josep Tabernero, Elena Elez, Jose A Seoane.
      The incidence of colorectal cancer (CRC) is rising rapidly in people younger than 50 years. Although this increase parallels shifts in lifestyle and environmental factors-collectively termed the exposome-whether these are indeed linked to the development of early-onset CRC (EOCRC) remains uninvestigated. Due to limited exposome data in most cancer cohorts, we constructed weighted methylation risk scores as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC compared to late-onset CRC (LOCRC) patients diagnosed at ≥70 years. Our analysis confirmed previously identified risk factors, including educational attainment, diet and smoking habits. Moreover, we identified exposure to the herbicide picloram as a new risk factor (adjusted P = 4.4 × 10-4) in the discovery cohort (31 EOCRC versus 100 LOCRC), which was replicated in a meta-analysis comprising nine CRC cohorts (P = 3.1 × 10-3; adjusted P = 1.5 × 10-2; 83 EOCRC versus 272 LOCRC). Subsequently, we analyzed population-based data from 94 US counties over 21 years and validated the association between picloram use and EOCRC incidence (P = 4.52 × 10-4), which remained significant after adjusting for socioeconomic factors and other pesticide use. These findings highlight the critical role of the exposome in EOCRC risk, underscoring the urgency for targeted personal and policy-level interventions.
    DOI:  https://doi.org/10.1038/s41591-026-04342-5
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