bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–01–12
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. NAC regulates metabolism and cell fate in intestinal stem cells.
  2. Crypt density and recruited enhancers underlie intestinal tumour initiation.
  3. H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium.
  4. Prognostic implications and therapeutic opportunities related to CAF subtypes in CMS4 colorectal cancer: insights from single-cell and bulk transcriptomics.
  5. Mutational and co-mutational landscape of early onset colorectal cancer.
  6. Intestinal Foxl1+ cell-derived CXCL12 maintains epithelial homeostasis by modulating cellular metabolism.
  7. METTL3 modulates colonic epithelium integrity via maintaining the self-renewal and differentiation of Lgr5+ stem cell.
  8. ALDOA contributes to colorectal tumorigenesis and metastasis by targeting YAP.
  1. Sci Adv. 2025 Jan 10. 11(2): eadn9750
    NAC regulates metabolism and cell fate in intestinal stem cells.
    Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.
      Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
    DOI:  https://doi.org/10.1126/sciadv.adn9750
  2. Nature. 2025 Jan 08.
    Crypt density and recruited enhancers underlie intestinal tumour initiation.
    Liam Gaynor, Harshabad Singh, Guodong Tie, Krithika Badarinath, Shariq Madha, Andrew Mancini, Swarnabh Bhattacharya, Mikio Hoshino, Frederic J de Sauvage, Kazutaka Murata, Unmesh Jadhav, Ramesh A Shivdasani.
      Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas3, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-08573-9
  3. Nat Cell Biol. 2025 Jan 08.
    H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium.
    Alison R S Pashos, Anne R Meyer, Cameron Bussey-Sutton, Erin S O'Connor, Mariel Coradin, Marilyne Coulombe, Kent A Riemondy, Sanjana Potlapelly, Brian D Strahl, Gunnar C Hansson, Peter J Dempsey, Justin Brumbaugh.
      Plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration. While precise gene expression controls these processes, the regulatory mechanisms that restrict or promote cell plasticity are poorly understood. Here we use the mouse small intestine as a model system to study cell plasticity. We find that H3K36 methylation reinforces expression of cell-type-associated genes to maintain specialized cell identity in intestinal epithelial cells. Depleting H3K36 methylation disrupts lineage commitment and activates regenerative gene expression. Correspondingly, we observe rapid and reversible remodelling of H3K36 methylation following injury-induced regeneration. These data suggest a fundamental role for H3K36 methylation in reinforcing specialized lineages and regulating cell plasticity and regeneration.
    DOI:  https://doi.org/10.1038/s41556-024-01580-y
  4. Apoptosis. 2025 Jan 04.
    Prognostic implications and therapeutic opportunities related to CAF subtypes in CMS4 colorectal cancer: insights from single-cell and bulk transcriptomics.
    Mengke Ma, Jin Chu, Changhua Zhuo, Xin Xiong, Wenchao Gu, Hansheng Li, Midie Xu, Dan Huang.
      Cancer-associated fibroblasts (CAFs) significantly influence tumor progression and therapeutic resistance in colorectal cancer (CRC). However, the distributions and functions of CAF subpopulations vary across the four consensus molecular subtypes (CMSs) of CRC. This study performed single-cell RNA and bulk RNA sequencing and revealed that myofibroblast-like CAFs (myCAFs), tumor-like CAFs (tCAFs), inflammatory CAFs (iCAFs), CXCL14+CAFs, and MT+CAFs are notably enriched in CMS4 compared with other CMSs of CRC. Multiplex immunohistochemistry was used to validate the distribution of CAF subtypes in patients with different CMSs. Prognosis-related CAF subtypes were identified, leading to the selection of four key genes (COL3A1, COL1A2, GEM, and TMEM47). Through machine learning, we developed a CAF poor-prognosis gene (CAFPRG) model to predict outcomes of patients with CMS4. High levels of CAFPRGs were identified as independent poor-risk factors for prognosis (p < 0.001). Tumors with elevated CAFPRGs exhibited increased infiltration of immune-suppressive cells and resistance to chemotherapy. The expression of these key genes was confirmed to be significantly higher in CAFs than in normal fibroblasts (NFs). Therefore, CAFPRGs may be valuable for precisely predicting patient survival and may present potential therapeutic opportunities for CMS4 CRC.
    Keywords:  CAF heterogeneity; Colorectal cancer; Consensus molecular subtypes; Machine learning; scRNA-seq
    DOI:  https://doi.org/10.1007/s10495-024-02063-z
  5. Biomarkers. 2025 Jan 09. 1-13
    Mutational and co-mutational landscape of early onset colorectal cancer.
    Jumanah Yousef Alshenaifi, Guglielmo Vetere, Giulia Maddalena, Mahmoud Yousef, Michael G White, John Paul Shen, Eduardo Vilar, Christine Parseghian, Arvind Dasari, Van Karlyle Morris, Ryan Huey, Michael J Overman, Robert Wolff, Kanwal P Raghav, Jason Willis, Kristin Alfaro, Andy Futreal, Y Nancy You, Scott Kopetz.
       INTRODUCTION: Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.
    METHODS: Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).
    RESULTS: EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations were more prevalent in LOCRC. Stratification by tumor site and MSI status highlighted significant location- and age-specific molecular differences, such as increased KRAS and CTNNB1 mutations in right-sided EOCRC and higher BRAF prevalence in MSI-H LOCRC (47% vs. 6.7%, p < 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of FBXW7 with NOTCH3, RB1, and PIK3R1.
    CONCLUSION: This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications.
    Keywords:  APC; Early-onset colorectal cancer; NGS; TP53; late-onset colorectal cancer; next-generation sequencing
    DOI:  https://doi.org/10.1080/1354750X.2024.2447089
  6. Int Immunol. 2025 Jan 08. pii: dxae068. [Epub ahead of print]
    Intestinal Foxl1+ cell-derived CXCL12 maintains epithelial homeostasis by modulating cellular metabolism.
    Mayu Yagita-Sakamaki, Takayoshi Ito, Taiki Sakaguchi, Shuichi Shimma, Bo Li, Daisuke Okuzaki, Daisuke Motooka, Shota Nakamura, Koji Hase, Eiichiro Fukusaki, Akira Kikuchi, Takashi Nagasawa, Atsushi Kumanogoh, Kiyoshi Takeda, Hisako Kayama.
      Several mesenchymal cell populations are known to regulate intestinal stem cell (ISC) self-renewal and differentiation. However, the influences of signaling mediators derived from mesenchymal cells other than ISC niche factors on epithelial homeostasis remain poorly understood. Here, we show that host and microbial metabolites, such as taurine and GABA, act on PDGFRαhigh Foxl1high sub-epithelial mesenchymal cells to regulate their transcription. In addition, we found that CXCL12 produced from Foxl1high sub-epithelial mesenchymal cells induces epithelial cell cycle arrest through modulation of the mevalonate-cholesterol synthesis pathway, which suppresses tumor progression in ApcMin/+ mice. We identified that Foxl1high sub-epithelial cells highly express CXCL12 among colonic mesenchymal cells. Foxl1-cre; Cxcl12f/f mice showed an increased number of Ki67+ colonic epithelial cells. CXCL12-induced Ca2+ mobilization facilitated phosphorylation of AMPK in intestinal epithelial cells, which inhibits the maturation of SREBPs that are responsible for mevalonate pathway activation. Furthermore, Cxcl12 deficiency in Foxl1-expressing cells promoted tumor development in the small and large intestines of ApcMin/+ mice. Collectively, these results demonstrate that CXCL12 secreted from Foxl1high mesenchymal cells manipulates intestinal epithelial cell metabolism, which links to the prevention of tumor progression in ApcMin/+ mice.
    DOI:  https://doi.org/10.1093/intimm/dxae068
  7. J Mol Cell Biol. 2025 Jan 06. pii: mjae060. [Epub ahead of print]
    METTL3 modulates colonic epithelium integrity via maintaining the self-renewal and differentiation of Lgr5+ stem cell.
    Chenbo Ding, Xinhui Yang, Hua Liu, Manolis Roulis, Huifang Chen, Yunzhu Chen, Hao Xu, Yimeng Gao, Jie Zhong, Hua-Bing Li, Youqiong Ye, Wei Cai, Weiguo Hu, Zhengting Wang.
      The development and homeostasis of intestinal epithelium are mediated by actively proliferating Lgr5+ stem cells, which possess a remarkable self-renewal and differentiation capacity. Recently, our study demonstrated that m6A methylation was essential for the survival of colonic stem cells. Here, we show that METTL3 expression is downregulated in the colon mucosa in ulcerative colitis (UC) patients and strongly associated with the differentiation and maturation of goblet cells during inflammation. In mice, depletion of Mettl3 significantly inhibits the self-renewal and differentiation of Lgr5+ stem cells, especially the differentiation and maturation of goblet cells, resulting in intestinal dysplasia and spontaneous inflammation. Mechanistically, Mettl3 deletion-mediated m6A loss facilitates the expression levels of Grb10 and Ifrd1 via increasing their mRNA stability. We further demonstrate that the levels of GRB10 and IFRD1 are negatively correlated with METTL3 level in UC samples. Collectively, our data indicate that METTL3 enhances the self-renewal and differentiation of Lgr5+ stem cells during intestinal development and inflammation, and thus it may be a potential therapeutic target for UC treatment.
    Keywords:  GRB10; IFRD1; Lgr5+ stem cell; METTL3; inflammation; intestinal development
    DOI:  https://doi.org/10.1093/jmcb/mjae060
  8. Cell Death Discov. 2025 Jan 05. 10(1): 489
    ALDOA contributes to colorectal tumorigenesis and metastasis by targeting YAP.
    Liang Sun, Ting Lu, Linhua Jiang, Huihui Yao, Qixuan Xu, Jie Sun, Xiaoqin Yang, Songbing He, Xinguo Zhu.
      Metabolic reprogramming is considered one of the hallmarks of cancer in which cancer cells reprogram some of their metabolic cascades, mostly driven by the specific chemical microenvironment in cancer tissues. The altered metabolic pathways are increasingly being considered as potential targets for cancer therapy. In this view, Aldolase A (ALDOA), a key glycolytic enzyme, has been validated as a candidate oncogene in several cancers. The current study aimed to investigate the role of ALDOA in the initiation and development of colorectal cancer (CRC). In this study, we observed an elevated expression of ALDOA in human CRC tissues and a positive correlation of elevated ALDOA expression with tumor size, invasion depth, LNM, and TNM stage. Kaplan-Meier analysis revealed that elevated ALDOA levels correlated with a poor prognosis in CRC patients with stage I-III, whereas the prognosis tends to be favorable in patients with advanced CRC. In addition, loss of function and gain of function experiments showed that ALDOA promoted CRC cell proliferation and migration in vitro and in vivo. Mechanistically, high ALDOA expression inhibited AMP-activated protein kinase (AMPK) phosphorylation possibly through regulating cellular glycolysis or the formation of v-ATPase-regulator-AXIN/LKB1 complex, which led to Yes-associated protein (YAP) unphosphorylation and enhanced the proliferative and migratory potential of CRC cells. Finally, the positive correlation between ALDOA and YAP signaling was also confirmed in clinical CRC tissues and the public data. Herein, ALDOA was identified to be a new metabolic regulator of YAP that suppresses the activation of AMPK signaling. This could suggest a novel avenue for treating CRC by inhibiting both ALDOA and YAP signaling.
    DOI:  https://doi.org/10.1038/s41420-024-02249-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒14 at 14:54.