bims-instec 2026-09-13 papers

bims-instec

Biomed News

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

Issue of 2026–09–13
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Zebrafish sox9b+ cells function as intestinal stem cells for epithelial homeostasis and regeneration.
Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.
Fatty acid shifts the cellular composition of small intestinal organoids towards a secretory cell lineage.
Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.
Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
Oncofetal reprogramming and cellular plasticity in colorectal cancer: from mechanisms to clinical translation.
Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.
Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis.
Heterotypic tumor microenvironments mirror dynamic wound-healing process.
Spatial membrane lipid remodelling encodes epithelial lineage and state in human colon cancer.
From drug response to resistance evolution: Leveraging 3D cancer models for functional precision oncology.

Cell Rep. 2026 Sep 10. pii: S2211-1247(26)01042-9. [Epub ahead of print]45(9): 117964

Zebrafish sox9b+ cells function as intestinal stem cells for epithelial homeostasis and regeneration.

Guozhen Wu, Xiangyong Wei, Liqi Zhang, Bangzhuo Huang, Jialong Fu, Jieqiong Zhao, Yanbo Huang, Xinmiao Tan, Xue Ma, Xiaoqian Fu, Jianbo He, Rui Ni, Qifen Yang, Lingfei Luo, Yun Yang.

  Intestinal stem cells (ISCs) are essential for maintaining epithelial homeostasis and driving tissue regeneration. The zebrafish intestine features a distinctive furrow-ruga architecture and lacks the crypt structures characteristic of mammalian intestines, leaving its ISC identity elusive. Characterizing zebrafish stem cell populations and their molecular markers is informative for intestinal physiology and evolution. Here, we identify sox9b+ cells residing within the proliferative zone of intestinal furrows as functional zebrafish ISCs. These cells contribute to epithelial turnover during homeostasis and can differentiate into nearly all characterized epithelial cell lineages. During epithelial regeneration, sox9b+ cells actively respond to injuries and constitute a major source of neogenic epithelium. Functional and transcriptomic analyses further establish sox9b as an essential factor of intestinal stemness and epithelial regeneration. Additionally, we observed that sox9b+ cells gradually acquire regional distribution patterns along the developing intestine. Our work provides a comparative model for understanding ISC function across diverse intestinal architectures.

Keywords:  CP: Stem cell research; homeostasis; intestinal stem cells; lineage tracing; regeneration; sox9b; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2026.117964
Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00375-7. [Epub ahead of print]97 104376

Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.

Kelly Ascenção, Olivia Oravecz, Csaba Szabo.

  Cancer stem cells (CSCs) contribute to therapeutic resistance, metastatic progression, and tumor recurrence, yet the metabolic pathways that sustain their survival remain incompletely understood. Here, we identify 3-mercaptopyruvate sulfurtransferase (3-MST), a hydrogen sulfide-producing enzyme encoded by MPST, as a metabolic dependency of colorectal CSCs. 3-MST expression was increased in human colorectal tumors and cancer cell lines and strongly correlated with proliferative capacity. HCT116-derived CSCs exhibited elevated 3-MST expression, increased hydrogen sulfide and reactive sulfur species production, altered membrane rigidity, and a metabolically restrained phenotype characterized by low basal oxidative phosphorylation and glycolysis. Genetic depletion of 3-MST preferentially impaired CSC proliferation, spheroid formation, stem-like properties, and migration, with less pronounced effects in differentiated parental cells. Pharmacological inhibition of 3-MST reproduced these effects across CSCs derived from several colorectal cancer cell lines and induced near-complete suppression of mitochondrial respiration and glycolytic activity. 3-MST inhibition also increased membrane fluidity, promoted cell death, and reduced CSC-derived tumor growth in mice. Integrated transcriptomic, proteomic, metabolomic, and lipidomic analyses demonstrated coordinated disruption of mitochondrial carbon metabolism, respiratory-chain maintenance, lipid desaturation, and membrane phospholipid homeostasis. These changes were accompanied by accumulation of free fatty acids and diacylglycerols and activation of antioxidants, integrated stress-response, endoplasmic-reticulum-stress, apoptotic, and p53-associated pathways. Ferroptosis-related molecular signatures were also enriched. These findings identify 3-MST as a critical regulator of colorectal CSC bioenergetics and membrane homeostasis and reveal a therapeutically exploitable metabolic vulnerability in treatment-resistant colorectal cancer.

Keywords:  3-Mercaptopyruvate sulfurtransferase; Bioenergetics; Colon cancer; Gasotransmitters; Hydrogen sulfide; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2026.104376
Mol Cell Endocrinol. 2026 Sep 07. pii: S0303-7207(26)00191-7. [Epub ahead of print]623 112914

Fatty acid shifts the cellular composition of small intestinal organoids towards a secretory cell lineage.

Jessica Chao, Giles O Best, Claire F Jessup, Damien J Keating, Alyce M Martin.

  Intestinal epithelial cells are highly sensitive to nutritional cues within the gut lumen. Although numerous studies have linked high-fat diets (HFD) to intestinal dysfunction, the mechanisms by which these diets alter epithelial cell composition to contribute to metabolic disease remain poorly understood. We used intestinal organoids to examine how exposure to a high-fat environment alters epithelial cell composition by quantifying the relative abundance of different epithelial cell types. We generated intestinal organoids using crypts isolated from C57BL/6 mouse small intestine. The organoids were exposed to free fatty acid, oleic acid (OA), for up to 7 days, and a multi-colour flow cytometry panel was used to assess changes in the density of different epithelial cell types. Changes in organoid morphology was assessed by measuring crypt depth and total organoid area. Exposure to OA significantly increased organoid size and crypt depth after 24 h. After 72 h, OA increased the proportion of transit amplifying cells and secretory progenitors, while reducing the density of absorptive cells and absorptive progenitors. The proportion of enteroendocrine and tuft cells also increased 3- and 7-days post OA treatment. Fatty acid exposure increases transit amplifying cell proliferation, which promotes organoid growth and crypt elongation. OA exposure shifted the differentiation trajectory of epithelial cells towards enteroendocrine and tuft cell fates. Given that enteroendocrine cell hormones regulate energy balance, understanding how dietary components alter the density of enteroendocrine cells could underscore the potential for diet-based therapies for the treatment of metabolic disease.

Keywords:  Enteroendocrine; Fatty acids; Obesity; Organoid

DOI:  https://doi.org/10.1016/j.mce.2026.112914
Gut. 2026 Sep 11. pii: gutjnl-2026-338390. [Epub ahead of print]

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

Ignacio Soriano, Kitty Sherwood, Joseph C Ward, Juan Fernandez-Tajes, Anusha Amanullah, Steve Thorn, Guler Gul, James F Wilson, Anders Isaksson, Bengt Glimelius, Tobias Sjöblom, Claire Palles, Ian Tomlinson.

   BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers.
OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits.
DESIGN: About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing.
RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation.
CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

Keywords:  COLONIC POLYPS; COLORECTAL CANCER GENES; DNA MICROSATELLITE INSTABILITY

DOI:  https://doi.org/10.1136/gutjnl-2026-338390
Nat Rev Cancer. 2026 Sep 08.

Reflecting on 25 years of cancer research: transformative advances and unmet expectations.

Allan Balmain, René Bernards, Hans Clevers, Karen H Vousden, Paul Workman, Marinka Zitnik.

DOI: https://doi.org/10.1038/s41568-026-00974-4
Front Oncol. 2026 ;16 1912866

Oncofetal reprogramming and cellular plasticity in colorectal cancer: from mechanisms to clinical translation.

Haoyu Wang, Songhao Liu, Mingxuan Zhang, Chunping Deng, Zhenguo Han.

  Colorectal cancer (CRC) progression and metastasis, as well as tolerance to therapy, are driven not only by genetic alterations but also by cell-state plasticity. Oncofetal reprogramming (OnF) refers to the reactivation of fetal intestinal developmental or injury-repair programs in tumor cells, thereby weakening adult lineage identity and enhancing the capacity for state transitions. Available evidence suggests that, in specific Wnt-dependent or APC-aberrant contexts, YAP/TAZ-TEAD and AP-1 may act cooperatively to establish and maintain the OnF state, whereas Wnt, EGFR-MAPK, FGF/FGFR, TGF-β, and extracellular matrix signaling contribute to its establishment and maintenance in a context-dependent manner. The OnF state can also intersect with epithelial-mesenchymal plasticity, dynamic stemness, drug-tolerant persister states, and immune and stromal niches, collectively increasing cellular heterogeneity, adaptability to therapy, and relapse potential in CRC. This review discusses the conceptual boundaries and operational criteria for identifying OnF in CRC, examines its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance, and emphasizes the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms. Further elucidation of the OnF state may facilitate biomarker development and anti-plasticity therapies, although its clinical translation will require standardized state classification and clinical validation.

Keywords:  AP-1; YAP/TAZ; cellular plasticity; colorectal cancer; drug tolerance; epithelial–mesenchymal plasticity; oncofetal reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1912866
Genes Dev. 2026 Sep 09.

Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.

Carolina Dehesa Caballero, Almut Schulze.

  Metabolic plasticity and flexibility are key characteristics that allow cancer cells to adapt and thrive in different environments. Specifically, cancer cells can dynamically change the routing of metabolic pathways in response to environmental changes and adapt their metabolic activity depending on local nutrient availability. The tumor microenvironment (TME) plays crucial roles in cancer development and progression. It is now widely accepted that different stromal cells, as well as soluble factors, including metabolites, derived from the TME support cancer cell proliferation and survival and drive migration, invasion, and the formation of metastases. Some cancer types grow in the proximity of adipose tissue (AT), which is mostly composed of mature adipocytes, a specialized cell type responsible for the storage and controlled release of lipids. In response to specific stimuli released by cancer cells, adipocytes can transform into cancer-associated adipocytes (CAAs). CAAs release signaling molecules, and provide fatty acids to cancer cells and other cell types in the TME, which can then utilize these fatty acids as fuel. The interaction between cancer cells and adipocytes creates a dynamic cross-talk that promotes disease progression through multiple mechanisms. In this review, we aim to provide an overview of the main factors in the CAA-cancer cell cross-talk, with a focus on the metabolic consequences of this interaction.

Keywords:  EMT; cancer-associated adipocytes; fatty acid transport; lipid droplets; metabolic flexibility and plasticity; metastasis; oxidative stress

DOI:  https://doi.org/10.1101/gad.353813.126
Elife. 2026 Sep 08. pii: RP110324. [Epub ahead of print]15

Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis.

Dana Naim, Zouheir Houhou, Florent Cauchois, Kevin Espie, Valerie Simon, Yvan Boublik, Francina Langa Vives, Zeinab Homayed, Conception Paul, Morgan Maillard, Michael Hahne, Julie Pannequin, Julie Nguyen, Audrey Sirvent, Serge Roche.

  Src-family kinases (SFKs) regulate proliferation in colonic epithelial cells (CECs), but the mechanisms that restrain their activity remain poorly defined. We identify Src-like adaptor protein (SLAP), a negative regulator of receptor tyrosine kinase signaling, as a key suppressor of SFK activity in the colon. Constitutive and inducible epithelial-specific Slap deletion using a villin-CreERT2 model increases CEC proliferation and accelerates tumorigenesis in the azoxymethane/dextran sodium sulfate model. Slap deficiency also enhances SFK-dependent expansion of normal and tumor-derived colonic organoids. Mechanistically, we identify the receptor tyrosine kinase EPHB2 as a critical upstream activator of SFKs and a direct target of SLAP-mediated regulation. Loss of Slap increased EphB2 protein abundance and tyrosine phosphorylation, and enhanced its association with active SRC. Pharmacological inhibition of EPHB2 suppressed SRC activation and reversed the hyperproliferative phenotype induced by Slap deficiency. Together, these findings uncover a non-genetic mechanism driving SFK activation during colonic transformation and establish SLAP as a tumor suppressor that constrains oncogenic EPHB2-SFK signaling in the colonic epithelium.

Keywords:  cancer biology; cell biology; celll signalling; colorectal cancer; human; intestine; mouse; oncogene; tumor supressor; tyrosine kinase

DOI:  https://doi.org/10.7554/eLife.110324
Trends Cancer. 2026 Sep 09. pii: S2405-8033(26)00203-7. [Epub ahead of print]

Heterotypic tumor microenvironments mirror dynamic wound-healing process.

Liqun Yu, Xiang H-F Zhang.

  Tumors co-opt normal wound-healing programs to shape their immune microenvironment, yet how distinct immune states arise and influence therapy remains unclear. Here, we synthesize emerging evidence that tumors become locked in either proinflammatory or pro-resolution phases, defined by neutrophil- or macrophage-dominated ecosystems. These states not only remodel local tissues but also systemically reprogram hematopoiesis, creating self-reinforcing immune circuits that drive progression, metastasis, and treatment resistance. We highlight recent advances linking epithelial-mesenchymal plasticity, lipid metabolism, and myeloid dynamics into an integrated 'wound-healing clock' model. This framework provides a conceptual basis for patient stratification and suggests that therapeutically redirecting immune states may unlock new strategies to overcome resistance across cancer types.

Keywords:  myeloid plasticity; therapy resistance; tumor microenvironment; wound healing

DOI:  https://doi.org/10.1016/j.trecan.2026.08.007
EBioMedicine. 2026 Sep 10. pii: S2352-3964(26)00357-9. [Epub ahead of print]132 106473

Spatial membrane lipid remodelling encodes epithelial lineage and state in human colon cancer.

Ramon M Rodriguez, Karim Pérez-Romero, Albert Maimó-Barceló, Teresa Ximelis, Cristina Huergo-Baños, Marcos A Martínez, Juan José Segura-Sampedro, Rafael Morales-Soriano, Cristina Pineño-Flores, Álvaro García-Granero, Sebastián Jerí, Ana M Aransay, José A Fernández, Gwendolyn Barceló-Coblijn.

   BACKGROUND: Cancer progression is driven by spatially organised intratumoural heterogeneity, yet the molecular basis of this organisation remains incompletely understood. While spatial transcriptomics has advanced rapidly, the spatial architecture and functional relevance of tumour lipid metabolism remain poorly characterised. We aimed to resolve whether membrane phospholipid remodelling is spatially organised across epithelial cell states in human colon cancer.
METHODS: We developed an integrative spatial multi-omic strategy linking mass spectrometry imaging to transcriptome-defined cellular states on consecutive tissue sections from primary and intraperitoneal metastatic human colon cancer specimens. Epithelial lipid phenotypes were characterised, validated in an independent cohort, and linked to transcriptional programmes.
FINDINGS: We identified four spatially organised epithelial lipid phenotypes defined by membrane phospholipid composition. These phenotypes aligned with transcriptional programmes reflecting epithelial lineage and differentiation state, and were organised along a differentiation axis marked by coordinated remodelling of arachidonic acid-, oleic acid-, and linoleic acid-containing phospholipids. Secretory-associated states, enriched in metastatic lesions, showed increased DHA-containing phospholipids and activation of peroxisomal pathways. Lipid phenotype assignments were reproducible across an independent cohort.
INTERPRETATION: Membrane phospholipid composition encodes biologically meaningful epithelial cell states within human tumours, establishing lipid remodelling as a structured and spatially organised dimension of tumour heterogeneity.
FUNDING: This study was supported by the ISCIII (PI19/00002, PI24/00313), the Health Research Institute of the Balearic Islands (IMP22/04), the Government of the Balearic Islands (AP_2021_001), the Basque Government (IT1491-22), the European Regional Development Fund, and the Scientific Foundation, Spanish Association Against Cancer (INVES222995RODR).

Keywords:  Colorectal cancer; Intratumoural heterogeneity; Mass spectrometry imaging; Phospholipid remodelling; Spatial lipidomics

DOI:  https://doi.org/10.1016/j.ebiom.2026.106473
Cancer Treat Rev. 2026 Aug 18. pii: S0305-7372(26)00116-7. [Epub ahead of print]150 103202

From drug response to resistance evolution: Leveraging 3D cancer models for functional precision oncology.

Alena Opattova, Katie Jean Znidericz, Giulia Chiabotto, Kristi Buzo, Sabrina Arena.

  Therapy resistance remains a major cause of relapse and cancer-related mortality, arising from dynamic interactions between tumor-intrinsic programs and microenvironmental constraints. Genetic and epigenetic alterations, transcriptional rewiring, metabolic adaptation, extracellular matrix signalling, hypoxia and limited drug penetration shape resistant phenotypes and therapeutic failure. Accurately modelling these processes is essential for identifying actionable resistance mechanisms and guide patient treatment. Conventional 2D cultures provide valuable mechanistic insights and scalable drug screening platforms, but fail to recapitulate the spatial organization, diffusion gradients and heterogeneous drug exposure characteristic of solid tumors. In contrast, advanced 3D preclinical models capture key aspects of tumor architecture and microenvironmental complexity that influence therapy response and resistance evolution. This review provides a comparative analysis of current 3D cancer models and proposes a conceptual framework linking mechanisms of therapeutic adaptation to the experimental platforms that most faithfully recapitulate them, with particular emphasis on patient-derived organoids (PDOs). By retaining clinically relevant features of the tumor of origin, PDOs enable the investigation of resistance evolution in both treatment-naïve and clinically treated tumors, as well as modelling experimentally acquired resistance through controlled therapeutic selection. These features enable mechanistic studies with high translational relevance, while supporting the development of precision oncology strategies. Finally, we propose practical recommendations for experimental design, model selection and reporting to improve reproducibility and facilitate cross-study comparisons. Collectively, advanced 3D cancer models represent a promising translational framework for uncovering mechanisms of therapy resistance and identifying actionable vulnerabilities that may guide more effective and personalized treatment strategies.

Keywords:  3D models; chemotherapy; drug resistance; high-throughput drug screening; microfluidics; organoids; spheroids

DOI:  https://doi.org/10.1016/j.ctrv.2026.103202