bims-instec 2026-04-19 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2026–04–19
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Western diet suppresses canonical intestinal stem cells and reprograms c-Kit⁺ reserve stem cells via proinflammatory dysbiosis.
Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
Dedifferentiation-driven oncogenic stemness promotes tumor-sustaining adaptability in the intestinal epithelium.
Stromal biomarker-based framework for identifying pMMR/MSS and dMMR/MSI colorectal cancers with poor outcomes and limited benefit from immunotherapy.
Cell death in cancer.
Clonal biases dictate availability of colonic cancer driver mutations for transformation.
Mapping intratumor heterogeneity across layers for advancing immunotherapy.
SnapShot: The hallmarks of cancer treatment.
Early-onset colorectal cancer: rising rates require rising awareness.
The metabolic profiles of cancer stem cells.
Carbohydrate responsive element binding protein promotes colorectal carcinogenesis via Wnt/β-catenin pathway.
Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.

bioRxiv. 2026 Apr 09. pii: 2026.04.06.716383. [Epub ahead of print]

Western diet suppresses canonical intestinal stem cells and reprograms c-Kit⁺ reserve stem cells via proinflammatory dysbiosis.

Sara Silva, Paola Procopio, Valeriya Zinina, Rafael R Segura Munoz, Seyram Segbefia, Sena Bae, Lior Lobel, Luigi Nardella, Andrea Sacchetti, Rosalie Joosten, Mathijs P Verhagen, Fatma Aktuna, Kim Pauck, Victor Sourjik, Holger Garn, Richard S Blumberg, Jens Puschhof, Wendy S Garrett, Riccardo Fodde, Mark Schmitt.

Dietary patterns are major determinants of colorectal cancer risk, yet how nutritional cues are molecularly integrated to reprogram intestinal stem cell identity and fuel tumor initiation is not well understood. Here, we demonstrate that a Western-style diet (WSD) rapidly and reversibly reprograms intestinal stem cell identity. WSD suppresses canonical Lgr5 ⁺ stem cells while enhancing epithelial proliferation and stemness through activation of alternative stem cell states in Paneth and deep crypt secretory (DCS) cells in the small and large intestine, respectively. These diet-reprogrammed cells exhibit inflammatory and genotoxic stress and yet remain proliferative, suggesting increased susceptibility to tumor-initiating mutations. Mechanistically, WSD-induced remodeling is mediated by the gut microbiota, specifically through the expansion of enterotoxigenic Bacteroides fragilis (ETBF). ETBF and its secreted toxin fragilysin suppress Lgr5 ⁺ stem cells while directly promoting multipotency of c-Kit ⁺ DCS cells via Wnt signaling. Collectively, our findings identify diet-driven gut microbial shifts as a key regulator of stem cell plasticity, linking environmental exposure to epithelial reprogramming and colorectal cancer risk.

DOI: https://doi.org/10.64898/2026.04.06.716383
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
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
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
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
Nat Commun. 2026 Apr 16.

Clonal biases dictate availability of colonic cancer driver mutations for transformation.

Nefeli Skoufou-Papoutsaki, Richard Kemp, Sam Adler, Kate Marks, Anne-Claire Girard, Shenay Mehmed, Filipe C Lourenço, Elisa B Moutin, Rogier Ten Hoopen, Edward Morrissey, Douglas J Winton, David S Tourigny.

Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (APC, KRAS, TP53, FBXW7 and CTNNB1) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that FBXW7 R465C mutations preferentially become fixed within the tissue, whereas KRAS G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both APC copies increasingly favours an APC-first pathway with age, while KRAS activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among KRAS mutant clones, with mixed lineage presentation observed only in a subset, a state linked to elevated transformation risk in other organs.

DOI: https://doi.org/10.1038/s41467-026-71944-5
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
Cell. 2026 Apr 16. pii: S0092-8674(26)00284-9. [Epub ahead of print]189(8): 2516-2516.e1

SnapShot: The hallmarks of cancer treatment.

Pietro Paolo Vitiello, Vito Amodio, Alberto Bardelli.

Cancer therapy evolved from cytotoxic chemotherapy to targeted and immune treatments guided by molecular profiling. Early cytotoxic drugs, rooted in mustard-gas observations, remain effective but toxic. Targeted agents exploit oncogenic vulnerabilities yet commonly select resistant clones. Checkpoint inhibitors and engineered modalities (ADCs, BiTEs, CAR-T) yield responses but are limited by toxicity and adaptive antigen loss. Future treatment combinations will require targeting the evolution of resistance. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.cell.2026.03.017
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
Stem Cell Res Ther. 2026 Apr 13.

The metabolic profiles of cancer stem cells.

Zuzana Tylichova, Borivoj Vojtesek, Philip J Coates.

  Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and therapeutic stress relies on a unique integration of energy flexibility, redox balance, and proteostatic programs. While bulk tumor cells typically favor aerobic glycolysis and high protein turnover, CSCs often exhibit elevated mitochondrial activity, fatty acid oxidation, and selective suppression of proteasome function. These metabolic features support quiescence, stress tolerance, and self-renewal. Beyond energy production, metabolic intermediates such as acetyl-CoA, succinate, and lactate serve as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity. Reactive oxygen species and antioxidant responses further tune this balance, shaping the transition between glycolytic and oxidative CSC states. These intrinsic programs are continuously influenced by the tumor microenvironment, where hypoxia, cytokine-driven signaling, and metabolic coupling with stromal and immune cells modulate CSC metabolism and reinforce stemness. Despite rapid progress, major conceptual and methodological gaps still limit our understanding of CSC metabolism and this review highlights these unresolved issues and further outline key contextual factors-including tumor-intrinsic, microenvironmental, systemic, and metastatic cues-that shape CSC metabolism and help explain the divergent observations reported across studies. Understanding this network will be essential for designing combinatorial therapies that target CSC metabolism while accounting for their heterogeneity and plasticity.

Keywords:  Cancer stem cells; Glucose; Glycolysis; Metabolism; Mitochondria; Proteasome

DOI:  https://doi.org/10.1186/s13287-026-05014-4
Oncogene. 2026 Apr 13.

Carbohydrate responsive element binding protein promotes colorectal carcinogenesis via Wnt/β-catenin pathway.

Ming Feng, Wenrui He, Guoxiao Ji, Lingfeng Tong, Zhangbing Chen, Yemin Zhu, Ying Lu, Na Tian, Qi Liu, Ping Zhang, Lukuan Zhang, Yakui Li, Xuemei Tong, Jian Meng, Lifang Wu.

Despite significant advances in colorectal cancer (CRC) diagnosis and treatment, drug therapy of CRC patients is still confronted with considerable challenges. Carbohydrate response element-binding protein (ChREBP), a glucose-responsive transcription factor regulating glycolysis and de novo lipogenesis, shows elevated expression in human CRC tissues and correlates with poor disease-free survival and overall survival. However, the in vivo role and mechanism of ChREBP in colorectal carcinogenesis remain unclear. We used ChREBP knockout mice, which were intraperitoneally injected with azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in drinking water. In the AOM/DSS-induced colorectal cancer model, carcinogenesis was reduced in ChREBP null mice. In the initial phases of colorectal carcinogenesis, ChREBP deficiency was associated with diminished epithelial cell proliferation and a lower number of aberrant crypt foci, but it had no impact on DNA damage or the severity of colitis. The key transcription factor β-catenin and Wnt target gene expression were both decreased in the colons of ChREBP null mice and in ChREBP-knockdown Caco-2 colorectal cancer cells. In vitro studies demonstrated that ChREBP overexpression promoted β-catenin accumulation, nuclear translocation, and transcriptional activity by interacting with β-catenin, while ChREBP knockdown produced the opposite effects. These findings establish a novel mechanism whereby ChREBP drives CRC progression through Wnt/β-catenin pathway activation, positioning it as both a potential therapeutic target and prognostic biomarker for CRC. Working model of ChREBP in promoting Wnt signaling and colorectal carcinogenesis. [Figure created with BioRender.com ].

DOI: https://doi.org/10.1038/s41388-026-03779-9
Mol Oncol. 2026 Apr 17.

Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.

Kanishka Tiwary, Jose Javier Bravo-Cordero.

  Metastasis remains the leading cause of cancer-related mortality. Even after major advances in early detection and systemic therapies, long-term disease recurrence frequently arises from the presence of dormant disseminated tumor cells (DTCs) at distant sites. Dormant DTCs disseminate from the primary tumor and reside in secondary organs in a reversible quiescent state characterized by minimal proliferation, enabling resistance to therapies that target actively dividing cells. Despite their inactivity, dormant DTCs are far from inert. Dormant DTCs dynamically interact with the surrounding tumor microenvironment (TME), including stromal, vascular, and immune components, to establish niches that maintain quiescence while limiting immune detection. While the mechanisms by which proliferating cancer cells evade immune surveillance have been extensively studied, the processes governing immune regulation, immune-mediated dormancy, and immune evasion of dormant DTCs remain incompletely integrated across literature. In this review, we explore recent advances describing how microenvironmental cues and immune pressures converge on tumor cell-intrinsic programs to sustain dormancy, promote immune tolerance, and enable long-term survival of DTCs across different organs and cancer types. We further discuss conditions that disrupt this equilibrium and drive escape from dormancy, as well as emerging therapeutic strategies aimed at eliminating or controlling dormant DTCs by targeting dormancy-specific immune and microenvironmental interactions.

Keywords:  disseminated tumor cells; immune evasion; metastatic niche; quiescence; tumor dormancy; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.70259