bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023‒05‒28
eight papers selected by
Maria-Virginia Giolito
Free University of Brussels

  1. Sci Adv. 2023 May 24. 9(21): eadc9660
      Adult stem cells are essential for tissue maintenance and repair. Although genetic pathways for controlling adult stem cells are extensively investigated in various tissues, much less is known about how mechanosensing could regulate adult stem cells and tissue growth. Here, we demonstrate that shear stress sensing regulates intestine stem cell proliferation and epithelial cell number in adult Drosophila. Ca2+ imaging in ex vivo midguts shows that shear stress, but not other mechanical forces, specifically activates enteroendocrine cells among all epithelial cell types. This activation is mediated by transient receptor potential A1 (TrpA1), a Ca2+-permeable channel expressed in enteroendocrine cells. Furthermore, specific disruption of shear stress, but not chemical, sensitivity of TrpA1 markedly reduces proliferation of intestinal stem cells and midgut cell number. Therefore, we propose that shear stress may act as a natural mechanical stimulation to activate TrpA1 in enteroendocrine cells, which, in turn, regulates intestine stem cell behavior.
  2. JCI Insight. 2023 May 23. pii: e167163. [Epub ahead of print]
      The incidence of early onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1AA98V, Rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9 and the mice were placed on either a high fat (HFD) or high sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however,19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes and Wnt/β-catenin signaling components in the HNF1A mutant relative to the wildtype mice. Mouse polyps and colon cancers from subjects carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared to wildtype HNF1A. Collectively, our study shows that the HNF1AA98V variant plus HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.
    Keywords:  Cancer; Colorectal cancer; Gastroenterology; Genetic variation; Genetics
  3. Nat Metab. 2023 May 22.
      Distinct niches of the mammalian gut are populated by diverse microbiota, but the contribution of spatial variation to intestinal metabolism remains unclear. Here we present a map of the longitudinal metabolome along the gut of healthy colonized and germ-free male mice. With this map, we reveal a general shift from amino acids in the small intestine to organic acids, vitamins and nucleotides in the large intestine. We compare the metabolic landscapes in colonized versus germ-free mice to disentangle the origin of many metabolites in different niches, which in some cases allows us to infer the underlying processes or identify the producing species. Beyond the known impact of diet on the small intestinal metabolic niche, distinct spatial patterns suggest specific microbial influence on the metabolome in the small intestine. Thus, we present a map of intestinal metabolism and identify metabolite-microbe associations, which provide a basis to connect the spatial occurrence of bioactive compounds to host or microorganism metabolism.
  4. Nat Commun. 2023 May 25. 14(1): 3025
      The cellular organization of gastrointestinal crypts is orchestrated by different cells of the stromal niche but available in vitro models fail to fully recapitulate the interplay between epithelium and stroma. Here, we establish a colon assembloid system comprising the epithelium and diverse stromal cell subtypes. These assembloids recapitulate the development of mature crypts resembling in vivo cellular diversity and organization, including maintenance of a stem/progenitor cell compartment in the base and their maturation into secretory/absorptive cell types. This process is supported by self-organizing stromal cells around the crypts that resemble in vivo organization, with cell types that support stem cell turnover adjacent to the stem cell compartment. Assembloids that lack BMP receptors either in epithelial or stromal cells fail to undergo proper crypt formation. Our data highlight the crucial role of bidirectional signaling between epithelium and stroma, with BMP as a central determinant of compartmentalization along the crypt axis.
  5. iScience. 2023 May 19. 26(5): 106623
      Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK's) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.
    Keywords:  Cell biology; Gastroenterology; Molecular biology
  6. Biofabrication. 2023 May 26.
      Despite encouraging progress in the development of in vitro cancer models, in vitro cancer models that simultaneously recapitulate the complexity of the tumor microenvironment and its diverse cellular components and genetic properties remain lacking. Here, an advanced vascularized lung cancer model is proposed, which includes patient-derived lung cancer organoids (LCOs), lung fibroblasts, and perfusable vessels using 3D bioprinting technology. To better recapitulate the biochemical composition of native lung tissues, a porcine lung-derived decellularized extracellular matrix (LudECM) hydrogel was produced to offer physical and biochemical cues to cells in the lung cancer microenvironment. In particular, idiopathic pulmonary fibrosis-derived lung fibroblasts (iLFs) were used to implement fibrotic niches similar to actual human fibrosis. It was shown that they increased cell proliferation and the expression of drug resistance-related genes in LCOs with fibrosis. In addition, changes in resistance to sensitizing targeted anti-cancer drugs in LCOs with fibrosis were significantly greater in LudECM than in that Matrigel. Therefore, assessment of drug responsiveness in vascularized lung cancer models that recapitulate lung fibrosis can help determine the appropriate therapy for lung cancer patients accompanied by fibrosis. Furthermore, it is expected that this approach could be utilized for the development of targeted therapies or the identification of biomarkers for lung cancer patients accompanied by fibrosis.
    Keywords:  3D bioprinting; lung fibrosis; lung tissue-specific bioinks; patient-derived lung cancer organoids; targeted anticancer drug testing; vascularized lung cancer models
  7. iScience. 2023 Jun 16. 26(6): 106600
      Mucinous colorectal adenocarcinoma (MC) is less likely to respond to chemotherapy and is associated with poorer prognosis compared with non-MC (NMC). Fibroblast activation protein (FAP) was found and validated to be upregulated in MC patients and was negatively correlated with prognosis and therapeutic outcomes in colorectal cancer (CRC) patients who were treated with adjuvant chemotherapy. Overexpression of FAP promoted CRC cell growth, invasion and metastasis, and enhanced chemoresistance. Myosin phosphatase Rho-interacting protein (MPRIP) was identified as a direct interacting protein of FAP. FAP may influence the efficiency of chemotherapy and prognosis by promoting the crucial functions of CRC and inducing tumor-associated macrophages (TAMs) recruitment and M2 polarization through regulating theRas Homolog Family Member/Hippo/Yes-associated protein (Rho/Hippo/YAP) signaling pathway. Knockdown of FAP could reverse tumorigenicity and chemoresistance in CRC cells. Thus, FAP may serve as a marker for prognosis and therapeutic outcome, as well as a potential therapeutic target to overcome chemoresistance in MC patients.
    Keywords:  Cancer; Cell biology; Immunology
  8. Cell Rep. 2023 May 17. pii: S2211-1247(23)00530-2. [Epub ahead of print] 112519
      Cancer chemoresistance is often attributed to slow-cycling persister populations with cancer stem cell (CSC)-like features. However, how persister populations emerge and prevail in cancer remains obscure. We previously demonstrated that while the NOX1-mTORC1 pathway is responsible for proliferation of a fast-cycling CSC population, PROX1 expression is required for chemoresistant persisters in colon cancer. Here, we show that enhanced autolysosomal activity mediated by mTORC1 inhibition induces PROX1 expression and that PROX1 induction in turn inhibits NOX1-mTORC1 activation. CDX2, identified as a transcriptional activator of NOX1, mediates PROX1-dependent NOX1 inhibition. PROX1-positive and CDX2-positive cells are present in distinct populations, and mTOR inhibition triggers conversion of the CDX2-positive population to the PROX1-positive population. Inhibition of autophagy synergizes with mTOR inhibition to block cancer proliferation. Thus, mTORC1 inhibition-mediated induction of PROX1 stabilizes a persister-like state with high autolysosomal activity via a feedback regulation that involves a key cascade of proliferating CSCs.
    Keywords:  CP: Cancer; NOX1; PROX1; autophagy; colon cancer; mTORC1; persister cells