bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–03–02
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
  2. An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration.
  3. Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins.
  4. Tumor-derived colorectal cancer organoids induce a unique Treg cell population by directing CD4+ T cell differentiation.
  5. Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
  6. Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
  7. Hybrid EMT Phenotype and Cell Membrane Tension Promote Colorectal Cancer Resistance to Ferroptosis.
  8. Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis.
  9. Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer.
  1. bioRxiv. 2025 Feb 16. pii: 2025.02.15.638423. [Epub ahead of print]
    Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
    Fangtao Chi, Qiming Zhang, Jessica E S Shay, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Sumeet Solanki, Yatrik M Shah, Judith Agudo, Ömer H Yilmaz.
      A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1101/2025.02.15.638423
  2. Development. 2025 Feb 27. pii: dev.204654. [Epub ahead of print]
    An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration.
    Maryam Marefati, Valeria Fernandez-Vallone, Morgane Leprovots, Gabriella Vasile, Frédérick Libert, Anne Lefort, Gilles Dinsart, Achim Weber, Jasna Jetzer, Marie-Isabelle Garcia, Gilbert Vassart.
      Collagenase/dispase treatment of intestinal tissue from adult mice generates cells growing in matrigel as stably replatable cystic spheroids in addition to differentiated organoids. Contrary to classical EDTA-derived organoids, these spheroids display poor intestinal differentiation and are independent of Rspondin/Noggin/EGF for growth. Their transcriptome resembles strikingly that of fetal intestinal spheroids, with downregulation of crypt base columnar cell (CBC) markers (Lgr5, Ascl2, Smoc2, Olfm4). In addition, they display upregulation of inflammatory and mesenchymal genetic programs, together with robust expression of YAP target genes. Lineage tracing, cell-sorting and single cell RNA sequencing experiments demonstrate that adult spheroid-generating cells belong to a hitherto undescribed developmental lineage, independent of Lgr5+ve CBCs, and are involved in regeneration of the epithelium following CBC ablation.
    Keywords:  Intestinal development; Organoids; Regeneration; Stem cells
    DOI:  https://doi.org/10.1242/dev.204654
  3. Cell Stem Cell. 2025 Feb 24. pii: S1934-5909(25)00042-6. [Epub ahead of print]
    Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins.
    Daisong Wang, Willem Kasper Spoelstra, Lin Lin, Ninouk Akkerman, Daniel Krueger, Talya Dayton, Jeroen S van Zon, Sander J Tans, Johan H van Es, Hans Clevers.
      BEST4/CA7+ cells of the human intestine were recently identified by single-cell RNA sequencing. While their gene expression profile predicts a role in electrolyte balance, BEST4/CA7+ cell function has not been explored experimentally owing to the absence of BEST4/CA7+ cells in mice and the paucity of human in vitro models. Here, we establish a protocol that allows the emergence of BEST4/CA7+ cells in human intestinal organoids. Differentiation of BEST4/CA7+ cells requires activation of Notch signaling and the transcription factor SPIB. BEST4/CA7+ cell numbers strongly increase in response to the cytokine interferon-γ, supporting a role in immunity. Indeed, we demonstrate that BEST4/CA7+ cells generate robust CFTR-mediated fluid efflux when stimulated with bacterial diarrhea-causing toxins and find the norepinephrine-ADRA2A axis as a potential mechanism in blocking BEST4/CA7+ cell-mediated fluid secretion. Our observations identify a central role of BEST4/CA7+ cells in fluid homeostasis in response to bacterial infections.
    Keywords:  BEST4/CA7(+) cells; bacterial infection; fluid homeostasis; human intestinal organoids; interferon-γ
    DOI:  https://doi.org/10.1016/j.stem.2025.02.003
  4. iScience. 2025 Feb 21. 28(2): 111827
    Tumor-derived colorectal cancer organoids induce a unique Treg cell population by directing CD4+ T cell differentiation.
    Sonia Aristin Revilla, Cynthia L Frederiks, Stefan Prekovic, Enric Mocholi, Onno Kranenburg, Paul J Coffer.
      In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells correlate with tumor development, immunotherapy failure, and poor prognosis. To assess how CRC tumors directly modulate Treg cell differentiation, we developed an in vitro co-culture system using CD4+ T cells from Foxp3eGFP mice and CRC tumor-derived organoids. Co-culture resulted in a significant increase in Treg cell numbers. RNA-sequencing identified a distinct transcriptional profile of CRC organoid-induced Treg cells, with upregulation of genes associated with CRC Treg cells in vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression-free intervals and overall survival in CRC patients. Human CRC organoids similarly induced Treg cells with enhanced suppressive capacity and upregulated genes linked to CRC Treg cells in vivo. This model provides insights into how CRC tumors modulate CD4+ T cell differentiation and can identify approaches to disrupt Treg cells and stimulate anti-tumor immunity.
    Keywords:  Cancer; Immune response; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.111827
  5. EMBO J. 2025 Feb 27.
    Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
    Ivana Paskov Škapik, Chiara Giacomelli, Sarah Hahn, Hanna Deinlein, Peter Gallant, Mathias Diebold, Josep Biayna, Anne Hendricks, Leon Olimski, Christoph Otto, Carolin Kastner, Elmar Wolf, Christina Schülein-Völk, Katja Maurus, Andreas Rosenwald, Nikolai Schleussner, Rene-Filip Jackstadt, Nicolas Schlegel, Christoph-Thomas Germer, Martin Bushell, Martin Eilers, Stefanie Schmidt, Armin Wiegering.
      Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2α (p-eIF2α). Despite increased protein synthesis rates following APC loss, eIF2α phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2α, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Bα and eIF2Bδ, two eIF2B subunits responsible for sensing p-eIF2α, impairs CRC viability, demonstrating that the eIF2B/p-eIF2α nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Bα subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Bα in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Bα as a target for clinical intervention. In conclusion, we demonstrate how the expression of the oncogenic signature in CRC is crucially controlled at the translational level.
    Keywords:  APC; Colorectal Cancer; Translation; eIF2B; eIF2α
    DOI:  https://doi.org/10.1038/s44318-025-00381-9
  6. Cancer Res. 2025 Feb 24.
    Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
    Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan.
      Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer (CRC) due to the deficiency of ornithine transcarbamylase (OTC). Accordingly, CRC cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of CRC to arginine deprivation, which dramatically decreased proliferation in CRC cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that CRC cells may be vulnerable to ferroptosis during arginine deprivation, and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1940
  7. Adv Sci (Weinh). 2025 Feb 22. e2413882
    Hybrid EMT Phenotype and Cell Membrane Tension Promote Colorectal Cancer Resistance to Ferroptosis.
    Xiaowei Wei, Yutong Ge, Yaolin Zheng, Sunyan Zhao, Yuhan Zhou, Yuhan Chang, Nuofan Wang, Xiumei Wang, Juan Zhang, Xuanchang Zhang, Liqiao Hu, Youhua Tan, Qiong Jia.
      Intratumoral heterogeneity, including epithelial-mesenchymal transition (EMT), is one major cause of therapeutic resistance. The induction of ferroptosis, an iron-dependent death, has the potential in overcoming this resistance to traditional treatment modalities. However, the roles of distinct EMT phenotypes in ferroptosis remain an enigma. This study reports that 3D soft fibrin microenvironment confers colorectal cancer (CRC) cells hybrid EMT phenotype and high level of resistance to ferroptosis. The activation of histone acetylation and WNT/β-catenin signaling drives this EMT phenotypic transition, which promotes the defense of 3D CRCs against ferroptosis via glutathione peroxidases/ferritin signaling axis. Unexpectedly, E-cadherin knockout in 3D but not 2D CRCs mediates an integrin β3 marked-late hybrid EMT state and further enhances the resistance to ferroptosis via integrin-mediated tension and mitochondrial reprogramming. The inhibition of integrin αvβ3-mediated tension and WNT/β-catenin-mediated hybrid EMT sensitizes 3D CRCs with and without E-cadherin deficiency to ferroptosis in vivo, respectively. Further, the EMT phenotype of patient-derived tumoroids is associated with CRC therapeutic resistance. In summary, this study uncovers previously unappreciated roles of hybrid EMT and cell membrane tension in ferroptosis, which not only predict the treatment efficacy but also potentiate the development of new ferroptosis-based targeted therapeutic strategies.
    Keywords:  colorectal cancer; ferroptosis; hybrid EMT; membrane tension; physical environment
    DOI:  https://doi.org/10.1002/advs.202413882
  8. Neoplasia. 2025 Feb 24. pii: S1476-5586(25)00019-3. [Epub ahead of print]61 101140
    Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis.
    Jing Chen, Shenghua Zhang, Xinmei Huang, Qianqian Wang, Weiyan Xu, Jing Huang, Yuming Su, Qinkun Sun, Xiaojuan Du, Baocai Xing, Xiaoyan Qiu.
       BACKGROUND: Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined.
    MATERIALS AND METHODS: Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation.
    RESULTS: Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling.
    CONCLUSION: Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis.
    Keywords:  Colorectal cancer liver metastasis; Erk; Sialylated IgG; c-Myc; p300
    DOI:  https://doi.org/10.1016/j.neo.2025.101140
  9. Cancer Res. 2025 Feb 24.
    Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer.
    Shenghe Deng, Jun Wang, Falong Zou, Denglong Cheng, Mian Chen, Junnan Gu, Jianguo Shi, Jia Yang, Yifan Xue, Zhengxin Jiang, Le Qin, Fuwei Mao, Xiaona Chang, Xiu Nie, Li Liu, Yinghao Cao, Kailin Cai.
      Obstructions can occur during any stage of colorectal cancer (CRC) and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared to non-obstructive CRC, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. Here, we found that CRC and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAFs). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts (NFs) but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF-1, TGF-β1 and CXCL8, which promoted the activation of NFs into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating CRC patients with risk of obstruction.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2892
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒17 at 12:16.