bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–02–22
six papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Myosin VB is critical for progenitor cell identity and function in the intestine.
  2. Intestinal stem cell damage caused by specific amino acid deprivation is linked to a potent integrated stress response triggered by the direct sensing of stem cells.
  3. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
  4. Colorectal cancer as a complex adaptive system: integrating the hallmarks of cancer with complexity theory.
  5. Systematic analysis of functional genetic and epigenetic variants in colorectal cancer.
  6. Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
  1. Stem Cell Reports. 2026 Feb 19. pii: S2213-6711(26)00031-7. [Epub ahead of print] 102820
    Myosin VB is critical for progenitor cell identity and function in the intestine.
    Andreanna Burman, Monica E Brown, Yilin Yang, Michael Momoh, Francisca Adeniran, Cynthia Ramos, Ken S Lau, Linda C Samuelson, Mitchell D Shub, Joseph T Roland, Izumi Kaji.
      Microvillus inclusion disease (MVID) is a congenital diarrheal disorder, caused by inactivating mutations in myosin Vb (MYO5B). MYO5B-deficient mice and cell lines have demonstrated the importance of MYO5B in brush border development; however, the previous models lacked specificity to test intestinal stem cell functions. In the present study, we investigated the effects of progressive MYO5B deficiency originating in intestinal crypt cells utilizing mouse models. Our transcriptomic and multiplex immunostaining datasets demonstrate that MYO5B is critical for intestinal stem cell function. MYO5B-deficient crypts acquire a hyperproliferative phenotype with incomplete cell differentiation in vivo and an elevated organoid formation rate compared to control crypts. An evident disruption in mitochondrial structure and fatty acid metabolism likely underlies these crypt phenotypes. Consistent with mouse models, MVID patient biopsies demonstrate abnormal expansion of the proliferative zone along with villus blunting. These data reveal the direct role of MYO5B in intestinal epithelial progenitor cell functions.
    Keywords:  MVID; differentiation; intestinal stem cell; microvillus inclusion disease; proliferation
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102820
  2. Biochem Biophys Res Commun. 2026 Feb 11. pii: S0006-291X(26)00218-4. [Epub ahead of print]807 153454
    Intestinal stem cell damage caused by specific amino acid deprivation is linked to a potent integrated stress response triggered by the direct sensing of stem cells.
    Ayumi Kozai, Takumi Satoh, Yoshiko Sugita-Konishi, Makoto Shimizu, Ken Iwatsuki, Miki Tadaishi, Kazuo Kobayashi-Hattori.
      Amino acid deprivation, particularly deficiencies in methionine (Met) or glutamine (Gln), disrupts intestinal stem cells (ISCs), causes growth suppression, and induces cell death. We previously found that among the branched-chain amino acid (BCAA), leucine and isoleucine deprivation maintain ISC survival, whereas valine (Val) deprivation induces ISC impairment, which is characterized by suppressed proliferation and increased cell death; however, the mechanisms underlying these divergent cell fates remain largely unclear. We here focused on the integrated stress response (ISR) as a regulator of cell fate under amino acid deprivation using mouse intestinal organoids and ISCs isolated from organoids. Deprivation of each BCAA uniformly suppressed global translation, whereas only Val deprivation induced activation through phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) and a persistent increase in the mRNA expressions of activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA damage-inducible 34, indicating a potent and sustained ISR. Analysis using ISCs isolated by cell sorting revealed that only Val deprivation markedly increased p-eIF2α levels and reduced organoid formation. Furthermore, Met and Gln deprivation resulted in similar responses to Val deprivation in organoids and isolated ISCs. Taken together, these results suggest that Val, Met, and Gln deprivation induce a potent ISR through direct sensing by ISCs, with the response associated with stem cell damage.
    Keywords:  Amino acids; Glutamine; Integrated stress response; Intestinal stem cells; Methionine; Organoids; Valine
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153454
  3. Dev Cell. 2026 Feb 17. pii: S1534-5807(26)00037-7. [Epub ahead of print]
    Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
    Jyotirekha Das, Saloni K Hombalkar, Alison D Klein, Esraa Nsasra, Muskaan Vasandani, Kay Petruzzi, Dajun Lu, Stephen Ruiz, Orit Kliper-Gross, Jiachen Hu, Michelle Riegman, Xuejun Jiang, Daniel A Heller, Assaf Zaritsky, Michelle S Bradbury, Michael Overholtzer.
      Ferroptosis is a lipid peroxide-dependent form of cell death that occurs in degenerative conditions and may be leveraged for cancer therapy. Although numerous regulators are known to control its cell-autonomous execution, ferroptosis also has a collective property that involves propagation between cells, and this regulation has remained more obscure. Different modes of ferroptosis induction involving inhibition of the anti-ferroptotic enzyme GPX4 or depletion of glutathione can impact the collective death response differently, but the mechanisms underlying "single-cell" versus "propagative" ferroptosis are not well understood. Here, we discover significant lysosome rupture occurring during propagative ferroptosis and identify glutathione depletion as sufficient to convert GPX4 inhibition from an individual-cell response to a collective response. We find that induction of single-cell ferroptosis involves heterogeneous death profiles, with necrosis and apoptosis occurring in parallel within cell populations. These findings identify factors that control propagation and underscore lysosomes as critical to the execution of ferroptosis.
    Keywords:  GPX4; TFEB; apoptosis; cathepsin; ferroptosis; iron; lipid peroxidation; lysosome; necrosis; propagation
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.014
  4. Front Oncol. 2025 ;15 1736140
    Colorectal cancer as a complex adaptive system: integrating the hallmarks of cancer with complexity theory.
    Luis R Basbus.
      The paradigm of the Hallmarks of Cancer, updated by Douglas Hanahan in 2022, represents one of the most influential syntheses for understanding the functional capabilities that sustain neoplastic transformation. However, its traditional interpretation, often reductionist and fragmentary, does not capture the non-linear, emergent, and adaptive dynamics of tumor behavior. This review proposes a reinterpretation of the hallmarks through the lens of complexity theory, conceptualizing colorectal cancer (CRC) as a self-organizing, open system operating far from equilibrium. Using an integrative conceptual approach, we map the ten classical hallmarks and the new dimensions proposed in 2022 (phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescence) onto the fundamental properties of complex systems: nonlinearity, emergence, feedback, openness, and historical dependence. We argue that CRC should not be understood as a simple sum of molecular alterations but as a dynamic network of interactions among cells, tissues, and microenvironments where global organization emerges from local rules. This systems-based perspective provides a conceptual foundation for translational models and integrative methodologies in oncology.
    Keywords:  colorectal cancer; complex systems; emergence; hallmarks of cancer; self-organization; systems biology
    DOI:  https://doi.org/10.3389/fonc.2025.1736140
  5. Sci Adv. 2026 Feb 20. 12(8): eaeb2473
    Systematic analysis of functional genetic and epigenetic variants in colorectal cancer.
    Erfei Chen, Qiqi Yang, Haoyang Dai, Yixin Chen, Yihui Zhang, Qianglong Wang, Rongrong Hou, Ming Chen, Jie Wang, Qianwen Xie, Wenju Sun, Yong-Qiang Ning, Ligang Fan, Jian Yan.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, yet the functional impact of noncoding variants on enhancer activity remains largely unexplored. In this study, we adapted and applied two high-throughput techniques, SNP-STARR-seq and Methyl-STARR-seq, to systematically evaluate the influence of 30,790 noncoding SNPs and more than 134,000 CpG sites on enhancer activity in primary and metastatic CRC cells. We identified 922 SNPs and 487 CpG-containing elements modulating enhancer activity in primary cells and found 3136 SNPs and 3008 methylation-sensitive elements with metastasis-specific regulatory effects. Multi-omics integration linked these variants to target genes, and CRISPR editing validated their roles in driving tumorigenic and metastatic phenotypes. Furthermore, we identified two CRC-specific hypermethylated loci, cg08640619 and cg25982657, as exceptional tissue-based early detection biomarkers (AUC > 0.96). Mechanistically, hypermethylation at cg08640619 disrupts RUNX2 binding, leading to inhibition of KIRREL1 and ETV3. Our study provides a comprehensive platform for understanding how genetic and epigenetic variants disrupt transcriptional programs in CRC, offering insights into disease susceptibility and identifying potential diagnostic and therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.aeb2473
  6. Cell. 2026 Feb 16. pii: S0092-8674(25)01502-8. [Epub ahead of print]
    Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
    Mohamad Assi, Ruohong Wang, Emily A Kawaler, Albert S W Sohn, M Zahidunnabi Dewan, Despoina Kalfakakou, Joel Encarnacion-Rosado, Kevin S Kapner, Koelina Ganguly, Joao A Paulo, Diane M Simeone, Andrew J Aguirre, Robert S Banh, Alec C Kimmelman.
      Autophagy, a programmed self-eating process, underlies the progression of multifactorial diseases like pancreatic ductal adenocarcinoma (PDA). Except for nutrient availability, the contribution of microenvironmental factors to autophagy regulation is not well understood. Through integrating functional genomics and tumor-like 3D cultures, we show that human PDA cells regulate their autophagy levels by sensing the extracellular matrix (ECM) via the integrinα3-Hippo-YAP1 axis. The spatial proximity of PDA cells to the ECM shapes their intracellular autophagy levels, leading to heterogeneous biological responses. Specifically, PDA cells with low autophagy levels are proliferative, whereas those with high autophagy levels display better tolerance to chemotherapies. Targeting the ECM-mediated autophagy regulation reduces autophagic heterogeneity, alters PDA growth, and shapes antitumor responses to FDA-approved therapies. In summary, we have characterized a non-metabolic regulation of autophagy through ECM sensing, opening the possibility to investigate and target ECM-specific outputs in diseases.
    Keywords:  autophagy; cancer; extracellular matrix sensing; fibrosis; lysosome
    DOI:  https://doi.org/10.1016/j.cell.2025.12.053
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