bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–10–27
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.
  2. USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.
  3. The GTPase RAB6 is required for stem cell maintenance and cell migration in the gut epithelium.
  4. p53 terminates the regenerative fetal-like state after colitis-associated injury.
  5. MOGAT3-Mediated DAG Accumulation Drives Acquired Resistance to Anti-BRAF/EGFR Therapy in BRAFV600E-Mutant Metastatic Colorectal Cancer.
  6. Intestinal tuft cells act as reserve stem cells after injury.
  7. A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
  8. Neoadjuvant combination immunotherapy in MSI/dMMR colorectal cancer.
  1. EMBO J. 2024 Oct 21.
    BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.
    Yehua Li, Xiaodan Wang, Meimei Huang, Xu Wang, Chunlin Li, Siqi Li, Yuhui Tang, Shicheng Yu, Yalong Wang, Wanglu Song, Wei Wu, Yuan Liu, Ye-Guang Chen.
      Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.
    Keywords:  BMP Signaling; Bcl11b; Colorectal Cancer; Intestinal Stem Cells; Wnt Signaling
    DOI:  https://doi.org/10.1038/s44318-024-00276-1
  2. Oncogene. 2024 Oct 23.
    USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.
    Michaela Reissland, Oliver Hartmann, Saskia Tauch, Jeroen M Bugter, Cristian Prieto-Garcia, Clemens Schulte, Sinah Loebbert, Daniel Solvie, Eliya Bitman-Lotan, Ashwin Narain, Anne-Claire Jacomin, Christina Schuelein-Voelk, Carmina T Fuss, Nikolett Pahor, Carsten Ade, Viktoria Buck, Michael Potente, Vivian Li, Gerti Beliu, Armin Wiegering, Tom Grossmann, Martin Eilers, Elmar Wolf, Hans Maric, Mathias Rosenfeldt, Madelon M Maurice, Ivan Dikic, Peter Gallant, Amir Orian, Markus E Diefenbacher.
      The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.
    DOI:  https://doi.org/10.1038/s41388-024-03141-x
  3. Development. 2024 Nov 01. pii: dev203038. [Epub ahead of print]151(21):
    The GTPase RAB6 is required for stem cell maintenance and cell migration in the gut epithelium.
    Pierre Simonin, Gehenna Lobo Guerrero, Sabine Bardin, Ram Venkata Gannavarapu, Denis Krndija, Joseph Boyd, Stephanie Miserey, Danijela Matic Vignjevic, Bruno Goud.
      Intestinal epithelial cells, which are instrumental in nutrient absorption, fluid regulation, and pathogen defense, undergo continuous proliferation and differentiation within the intestinal crypts, migrating towards the luminal surface where they are eventually shed. RAB GTPases are key regulators of intracellular vesicular trafficking and are involved in various cellular processes, including cell migration and polarity. Here, we investigated the role of RAB6 in the development and maintenance of the gut epithelium. We generated conditional knockout mice with RAB6 specifically deleted in the gut epithelium. We found that deletion of the Rab6a gene resulted in embryonic lethality. In adult mice, RAB6 depletion led to altered villus architecture and impaired junction integrity without affecting the segregation of apical and basolateral membrane domains. Further, RAB6 depletion slowed down cell migration and adversely affected both cell proliferation and stem cell maintenance. Notably, the absence of RAB6 resulted in a diminished number of functional stem cells, as evidenced by the rapid death of isolated crypts from Rab6a KO mice when cultured as 3D organoids. Together, these results underscore the essential role of RAB6 in maintaining gut epithelial homeostasis.
    Keywords:  Gut epithelium; Migration; Mouse models; RAB GTPases; Stem cells
    DOI:  https://doi.org/10.1242/dev.203038
  4. Sci Adv. 2024 Oct 25. 10(43): eadp8783
    p53 terminates the regenerative fetal-like state after colitis-associated injury.
    Kimberly Hartl, Şafak Bayram, Alexandra Wetzel, Christine Harnack, Manqiang Lin, Anne-Sophie Fischer, Lichao Liu, Giulia Beccaceci, Guido Mastrobuoni, Sabrina Geisberger, Martin Forbes, Benedict J E Monteiro, Martina Macino, Roberto E Flores, Cornelius Engelmann, Hans-Joachim Mollenkopf, Michael Schupp, Frank Tacke, Ashley D Sanders, Stefan Kempa, Hilmar Berger, Michael Sigal.
      Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.
    DOI:  https://doi.org/10.1126/sciadv.adp8783
  5. J Clin Invest. 2024 Oct 22. pii: e182217. [Epub ahead of print]
    MOGAT3-Mediated DAG Accumulation Drives Acquired Resistance to Anti-BRAF/EGFR Therapy in BRAFV600E-Mutant Metastatic Colorectal Cancer.
    Jiawei Wang, Huogang Wang, Wei Zhou, Xin Luo, Huijuan Wang, Qing Meng, Jiaxin Chen, Xiaoyu Chen, Yinqiang Liu, David W Chan, Zhenyu Ju, Zhangfa Song.
      BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-mutant mCRC improved clinical benefits; unfortunately, inevitable acquired resistance limits the treatment outcome, and the mechanism has not been validated. Here, we discovered that monoacylglycerol O-Acyltransferase 3 (MOGAT3) mediated diacylglycerol (DAG) accumulation contributed to acquired resistance to encorafenib/cetuximab by dissecting BRAFV600E-mutant mCRC patient-derived xenograft (PDX) model exposed to encorafenib/cetuximab administration. Mechanistically, upregulated MOGAT3 promotes DAG synthesis and reduces fatty acid oxidation (FAO)-promoting DAG accumulation and activating PKCα-CRAF-MEK-ERK, driving acquired resistance. Resistance-induced hypoxia promotes MOGAT3 transcriptional elevation; simultaneously, MOGAT3-mediated DAG accumulation increases HIF1A expression in translation level through PKCα-CRAF-eIF4E activation, strengthening the resistance status. Intriguingly, reducing intratumoral DAG by fenofibrate or Pf-06471553 restores the antitumor efficacy of encorafenib/cetuximab on resistant BRAFV600E-mutant mCRC, interrupted PKCα-CRAF-MEK-ERK signaling. These findings reveal the critical metabolite DAG as a modulator of encorafenib/cetuximab efficacy in BRAFV600E-mutant mCRC, suggesting that fenofibrate may prove beneficial for resistant BRAFV600E-mutant mCRC patients.
    Keywords:  Colorectal cancer; Drug therapy; Gastroenterology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI182217
  6. Nature. 2024 Oct 23.
    Intestinal tuft cells act as reserve stem cells after injury.
      
    Keywords:  Regeneration; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03383-5
  7. Cell. 2024 Oct 19. pii: S0092-8674(24)00903-6. [Epub ahead of print]
    A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
    Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang.
      The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.
    Keywords:  adaptation; breakfast skipping; in vivo metabolite tracing; metabolic heterogeneity; multi-omics; the small intestine; two-front nutrient supply; zonated function of enterocyte
    DOI:  https://doi.org/10.1016/j.cell.2024.08.012
  8. Trends Cancer. 2024 Oct 24. pii: S2405-8033(24)00225-5. [Epub ahead of print]
    Neoadjuvant combination immunotherapy in MSI/dMMR colorectal cancer.
    Meggy Suarez-Carmona, Niels Halama.
      Neoadjuvant immune checkpoint inhibition (ICI) is a new approach to treat patients with colorectal cancer (CRC). The effects of combined neoadjuvant ICI in locally advanced, DNA mismatch repair (dMMR)-deficient/microsatellite instable (MSI) CRC were recently reported by de Gooyer et al. from the NICHE-3 trial. Further studies will determine whether these impressive pathological responses lead to long-term clinical benefit.
    Keywords:  MSI; colorectal cancer; dMMR; immune checkpoint inhibition; neoadjuvant therapy
    DOI:  https://doi.org/10.1016/j.trecan.2024.10.006
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