bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–02–23
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid.
  2. Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation.
  3. Diet links gut chemistry with cancer risk in C57Bl/6 mice and human colorectal cancer patients.
  4. Mesenchymal Hippo signaling regulates intestinal homeostasis in adult mice.
  5. The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.
  6. Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer.
  7. YY1 as a mediator to enhance the resistance of KRAS mutant colorectal cancer cells to cetuximab.
  8. Five-gene expression signature associated with acquired FOLFIRI resistance and survival in metastatic colorectal cancer.
  9. Human colon stem cells are the principal epithelial responders to bacterial antigens.
  10. Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.
  1. Nat Microbiol. 2025 Feb 19.
    Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid.
    Shuning Zhang, Lihua Peng, Shyamal Goswami, Yuchen Li, Haiyue Dang, Shuli Xing, Panpan Feng, Giulia Nigro, Yingying Liu, Yingfei Ma, Tianhao Liu, Jiahua Yang, Tinglei Jiang, Yingnan Yang, Nick Barker, Philippe Sansonetti, Parag Kundu.
      Intestinal crypts harbour a specific microbiota but whether and how these bacteria regulate intestinal stem cells (ISCs) or influence colorectal cancer (CRC) development is unclear. Here we screened crypt-resident bacteria in organoids and found that indole acetic acid (IAA) secreted by Acinetobacter radioresistens inhibits ISC turnover. A. radioresistens inhibited cellular proliferation in tumour slices from CRC patients and inhibited intestinal tumorigenesis and spheroid initiation in APCMin/+ mice. Targeted clearance of A. radioresistens from colonic crypts using bacteriophage increased EphB2 expression and consequently promoted cellular proliferation, ISC turnover and tumorigenesis in mouse models of CRC. The protective effects of A. radioresistens were abrogated upon deletion of trpC to prevent IAA production, or upon intestine-specific aryl hydrocarbon receptor (AhR) knockout, identifying an IAA-AhR-Wnt-β-catenin signalling axis that promotes ISC homeostasis. Our findings reveal a protective role for an intestinal crypt-resident microbiota member in tumorigenesis.
    DOI:  https://doi.org/10.1038/s41564-025-01937-5
  2. bioRxiv. 2025 Feb 08. pii: 2025.02.07.636917. [Epub ahead of print]
    Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation.
    Swarnabh Bhattacharya, Guodong Tei, Pratik Narendra Pratap Singh, Ermanno Malagola, Onur Eskiocak, Ruiyang He, Judith Kraiczy, Wei Gu, Yakov Perlov, Semir Beyaz, Timothy Cragin Wang, Qiao Zhou, Ramesh Arjun Shivdasani.
      Enterocytes and four secretory cell types derive from stem cells located in intestinal crypts. Whereas secretory goblet and Paneth cells have long been considered distinct, we find high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of sibling enteroendocrine or tuft cells. Mouse and human goblet and Paneth cells express extraordinary fractions of selective antimicrobial genes, reflecting specific and variable gene responses to local niche signals. Wnt signaling retains few ATOH1+ secretory daughters in crypt bottoms, where an absence of BMP signaling potently induces Paneth features; those that move away from crypt bottoms acquire classic goblet properties. These post-mitotic cellular phenotypes and their underlying accessible cis-elements interconvert readily. Thus, goblet and Paneth properties represent alternative manifestations of a single versatile signal-responsive secretory cell. These findings reveal exquisite niche-dependent cell plasticity and the cis-regulatory dynamics of an updated unitarian model of the intestinal epithelial lineage.
    DOI:  https://doi.org/10.1101/2025.02.07.636917
  3. bioRxiv. 2025 Jan 28. pii: 2025.01.27.635083. [Epub ahead of print]
    Diet links gut chemistry with cancer risk in C57Bl/6 mice and human colorectal cancer patients.
    Ziv Cohen, Jiahn Choi, Karina Peregrina, Saad Khan, Sarah Wolfson, Cherrie Sherman, Leonard Augenlicht, Libusha Kelly.
       Background & Aims: Western-style diets, characterized by higher fat and protein, and low micronutrient levels, promote the development of colorectal cancer (CRC). Here, we investigate the role of a Western diet on microbiome composition, sulfide production, and intestinal epithelial damage in pre-CRC mice, and validate taxonomic changes in a meta-analysis of human CRC patients.
    Methods: NWD1 is a purified Western-style diet that produces sporadic intestinal and colon tumors in wild-type C57BL/6 mice in the absence of genetic or carcinogen exposure. To determine how this diet influences cancer risk by shaping microbial composition and sulfide chemistry, mice were fed NWD1 or a purified control diet for 24 weeks. Microbiome composition, sulfide production, and intestinal stem cell mRNA expression were assessed. Observed microbiome changes were validated in a human CRC meta-analysis.
    Results: Fecal sulfide levels were tripled in NWD1-fed mice ( P< 0.00001 ), concurrent with increased abundance of the sulfidogenic Erysipelotrichaceae family. NWD1-fed mice had increased expression of mitochondrial sulfide oxidation genes in Lgr5 hi intestinal stem cells, demonstrating an adaptive response to elevated sulfide. In a meta-analysis of human CRC studies, we observed that Erysipelotrichaceae were associated with CRC, validating both canonical CRC microbes such as Solobacterium moorei and highlighting the potential contribution of previously unrecognized, disease-associated microbes.
    Conclusions: Our analyses connect the risk factors of Western diet, sulfide, and epithelial damage in a pre-cancer mouse model to microbiome changes observed in human CRC patients and suggest that microbial signatures of CRC and gut ecosystem alteration may manifest long before disease development.
    DOI:  https://doi.org/10.1101/2025.01.27.635083
  4. iScience. 2025 Feb 21. 28(2): 111847
    Mesenchymal Hippo signaling regulates intestinal homeostasis in adult mice.
    Kyvan Dang, Alka Singh, Xin Chen, Jennifer L Cotton, Susu Guo, Xiaodi Hu, Zhipeng Tao, Haibo Liu, Lihua J Zhu, Y Tony Ip, Xu Wu, Junhao Mao.
      Intestinal homeostasis is tightly regulated by the reciprocal interaction between the gut epithelium and adjacent mesenchyme. The Hippo pathway is intimately associated with intestinal epithelial homeostasis and regeneration; however, its role in postnatal gut mesenchyme remains poorly defined. Here, we find that removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle layers has largely no effect; however, Hippo-YAP signaling in the niche-forming Gli1+ mesenchymal cells plays intrinsic roles in regulating intestinal homeostasis. We find that Lats1/2 deletion drives robust mesenchymal over-proliferation, and YAP activation in Gli1+ pericryptal cells disrupts the intestinal epithelial-mesenchymal crosstalk via promoting Wnt ligand production. We show that YAP is upregulated in the stroma during dextran sodium sulfate (DSS)-induced injury, and mesenchymal YAP activation facilitates intestinal epithelial regeneration. Altogether, our data suggest an important role for mesenchymal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis and pathogenesis.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.111847
  5. Cell Rep. 2025 Feb 11. pii: S2211-1247(25)00057-9. [Epub ahead of print] 115286
    The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.
    May Nakajima-Koyama, Mio Kabata, Joonseong Lee, Yuko Sogabe, Satoko Sakurai, Akira Hirota, Mizuki Kimura, Tomonori Nakamura, Yusuke Imoto, Kohei Kometani, Yoko Hamazaki, Yasuaki Hiraoka, Mitinori Saitou, Eisuke Nishida, Takuya Yamamoto.
      While the intestinal epithelium has the highest cellular turnover rates in the mammalian body, it is also considered one of the tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards intestinal stem cells (ISCs) from environmental conditions in the aged intestine. Using in vivo phenotypic analysis, transcriptomics, and in vitro intestinal organoid studies, we show that age-dependent activation of interferon-γ (IFN-γ) signaling and inactivation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling are responsible for establishing an equilibrium of Lgr5+ ISCs-between active and quiescent states-to preserve the ISC pool during aging. Furthermore, we show that differentiated cells have different sensitivities to each of the two signaling pathways, which may induce aging-related, functional, and metabolic changes in the body. Thus, our findings reveal an exquisitely balanced, age-dependent signaling mechanism that preserves stem cells at the expense of differentiated cells.
    Keywords:  CP: Stem cell research; ERK/MAPK signaling pathway; IFN-γ signaling pathway; aging; intestinal stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115286
  6. Nat Cancer. 2025 Feb 18.
    Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer.
    Qingguo Li, Yiwei Xiao, Lingyu Han, Wenqin Luo, Weixing Dai, Hongsheng Fang, Renjie Wang, Ye Xu, Sanjun Cai, Ajay Goel, Fan Bai, Guoxiang Cai.
      Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.
    DOI:  https://doi.org/10.1038/s43018-025-00910-9
  7. J Genet. 2025 ;pii: 3. [Epub ahead of print]104
    YY1 as a mediator to enhance the resistance of KRAS mutant colorectal cancer cells to cetuximab.
    Yi Ma, Yi Lin, Congying Wang, Yujie Lv, Wei Chen.
      Cetuximab has been indicated as the mainstay of metastatic colorectal cancer (CRC) therapy, of which application was impeded by chemoresistance that was casually attributed to KRAS mutation. This study sought to determine whether YY1 mediated the resistance of CRC cells harbouring KRAS mutation (KRASmut) to cetuximab. The expression of YY1 between cetuximab response and resistance was investigated in cancerous tissues from CRC patients received cetuximab therapy comprising eight KRAS wild-type (KRASwt) and 12 KRASmut. The relationship between YY1 expression and cetuximab resistance was explored based on KRASmut and KRASwt CRC cell lines. To explore the role of YY1 in the cetuximab resistance of KRASmut CRC cells, the response to cetuximab was investigated in cetuximab-resistant cells (SW620-R) with YY1 silence and cetuximab sensitive cells (HCT116) with YY1 overexpression. EGFR/Akt/ERK signalling activation, as well as mRNA and active GTP-bound KRAS level were assessed after the treatment. In KRASmut CRC tissues, YY1 expression was correlated with the histological grade and the cetuximab resistance. Significantly markable differences in YY1 expression between cetuximab-resistant and the parental cell lines were found in KRASmut cells. Silencing YY1 resensitized SW620-R cells to cetuximab and led to an elevation of the active GTP-binding KRAS. Conversely, the capability against cetuximab and GTP-binding KRAS activation of HCT116 cells was enhanced by overexpressing YY1. The blockage of EGFR/Akt/ERK signalling by cetuximab was re-observed in SW620-R cells after silencing YY1 but impaired in HCT116 by overexpressing YY1. The YY1 mediates the resistance of KRASmut CRC cells to cetuximab.
  8. Lab Invest. 2025 Feb 13. pii: S0023-6837(25)00017-0. [Epub ahead of print] 104107
    Five-gene expression signature associated with acquired FOLFIRI resistance and survival in metastatic colorectal cancer.
    Elise Pretzsch, Christiane A Peschel, Matjaz Rokavec, Lucien Torlot, Pan Li, Heiko Hermeking, Jens Werner, Frederick Klauschen, Jens Neumann, Andreas Jung, Jörg Kumbrink.
      FOLFIRI, a combination of folinic acid, 5-Fluorouracil, and Irinotecan, is one of the recommended first-line chemotherapeutic treatments for metastatic colorectal cancer (mCRC). Unfortunately, acquired FOLFIRI resistance represents a common obstacle in the treatment of mCRC patients. Thus, we aimed to identify mechanisms, gene alterations and gene expression signatures contributing to acquired FOLFIRI resistance by mimicking this problem in a cell culture model and subsequent translation in clinical datasets. Three FOLFIRI resistant CRC cell lines were established by continuous FOLFIRI treatment. Comparative mutation screening (161 genes) and transcriptomics (pathway and differential expression analyses) were performed in parental and resistant cells. Data reconciliation was performed in GSE62322, a clinical FOLFIRI responder dataset (intrinsic resistance). Relapse-free survival (RFS) associations of identified differentially expressed genes (DEGs) and potential gene signatures were investigated in eight clinical CRC datasets. No mutual genetic alterations were found in FOLFIRI resistant derivatives. Resistant cell lines displayed activation of MAPK, immune response and EMT pathways. 12 DEGs, significantly differentially expressed in at least two of the three resistant cell lines, were identified. Comparison with GSE62322 and subsequent survival analyses revealed a five-gene FOLFIRI signature comprised of CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated with RFS in multiple datasets including TCGA CRC (Hazard ratio (HR)=2.634, p=4.53x10-6), in pooled samples of all datasets (all stages (N=1981): HR=1.852, p=6.44x10-13; stage IV (N=260): HR=2.462, p=5.22x10-9). A multivariate Cox regression analysis identified the five-gene signature as an independent prognostic factor in the TCGA dataset (HR=1.89, p=0.0202). Our analyses revealed a five-gene FOLFIRI resistance signature associated with RFS that may help to predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance.
    Keywords:  FOLFIRI resistance; Metastatic colorectal cancer; biomarker; gene signature; survival
    DOI:  https://doi.org/10.1016/j.labinv.2025.104107
  9. bioRxiv. 2025 Feb 08. pii: 2025.02.07.637053. [Epub ahead of print]
    Human colon stem cells are the principal epithelial responders to bacterial antigens.
    Maaike Hillegonda de Vries, Claartje Meddens, Hemme Hijma, Anne-Claire Berrens, Suze Jansen, Berend Kooiman, Scott Snapper, Hans Clevers, Michal Mokry, Ewart Kuijk, Edward Nieuwenhuis.
      Intestinal epithelial cells (IECs) are capable of mounting an adequate antimicrobial inflammatory response to pathogens while tolerating commensals. The underlying regulatory mechanisms of immune sensitivity remain incompletely understood, particularly in the context of human IECs. To enhance our understanding of the immune response of IECs to bacterial epithelial barrier breach, we investigated whether epithelial responsiveness is contingent on cell identity and cell polarization. We exposed human intestinal organoids to bacterial antigens to study their immune responses. Notable discrepancies were observed in the specific reactions exhibited by intestinal stem cells (ISCs) and enterocytes. It was determined that basolateral exposure of IECs to bacterial antigens resulted in a robust response, whereas apical exposure elicited a significantly more modest response. We identified ISCs as the responders, while the reaction of enterocytes was found to be attenuated. The regulation of bacterial responsiveness in enterocytes occurs at multiple levels, including the modulation of NFκB activation and post-transcriptional control of mRNA stability. Our findings demonstrate that differentiated non-responsive enterocytes can be sensitized to bacterial antigens through the activation of the WNT pathway. These findings extend the crucial role of WNT signaling for intestinal epithelial homeostasis and regulation of stem cell maintenance, proliferation, differentiation, and tissue architecture in the gut. Additionally, they reveal a new function of WNT signaling in regulating microbial responses within the intestinal environment.
    DOI:  https://doi.org/10.1101/2025.02.07.637053
  10. IUBMB Life. 2025 Feb;77(2): e70007
    Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.
    Alejandro Lopez-Mejia, Angela Patricia Moreno-Londoño, Gabriela Fonseca Camarillo, Jesús Kazuo Yamamoto-Furusho, Juan Antonio Villanueva-Herrero, Jorge Luis de Leon-Rendón, Maria Cristina Castañeda Patlán, Martha Robles-Flores.
      Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1α, HIF-2α, and HIF-3α. However, in contrast to HIF-1α and HIF-2α, a specific role for HIF-3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3α in colon cancer. As reported previously for HIF-1α and HIF-2α, we found that HIF-3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3α displays high stability in cells compared with HIF-1α and HIF-2α. Progno Scan data analysis showed that overexpression of HIF-3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3α knockdown compared with control HIF-3α expressing cells. In addition, HIF-3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.
    Keywords:  HIF‐3α; colorectal cancer; hypoxia; hypoxia inducible factors
    DOI:  https://doi.org/10.1002/iub.70007
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