bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021‒12‒12
four papers selected by
Maria-Virginia Giolito

  1. Nat Commun. 2021 Dec 09. 12(1): 7150
      Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.
  2. Gastroenterology. 2021 Dec 06. pii: S0016-5085(21)03813-0. [Epub ahead of print]
      BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis.METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with BrdU dosing. RNA-sequencing of fluorescence-activated cell sorting (FACS)-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA-sequencing data and tissue microarray were used. CRC organoids were injected into the colon of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis.
    RESULTS: Our lineage-tracing studies revealed that, in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal Leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker we identified using RNA-sequencing. High MCAM expression induced by TGF-β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor-ĸB-IL34/CCL8 signaling that promotes macrophage chemotaxis.
    CONCLUSION: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.
    Keywords:  CD146; alpha-smooth muscle actin (αSMA); colorectal cancer; tumor microenvironment
  3. iScience. 2021 Dec 17. 24(12): 103444
      Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant transformation, and disease progression in the intestine remain incompletely understood. Here, we report, in agreement with previous findings, that activation of the Retinoic Acid Receptor and the Retinoid X Receptor results in enhanced transcription of enterocyte-specific genes in mouse small intestinal organoids. Conversely, inhibition of this pathway results in reduced expression of genes associated with the absorptive lineage. Strikingly, this latter effect is conserved in a human organoid model for colorectal cancer (CRC) progression. We further show that RXR motif accessibility depends on progression state of CRC organoids. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic target in CRC.
    Keywords:  Biological sciences; Cancer; Cell biology; Functional aspects of cell biology; Oncology
  4. Cell Cycle. 2021 Dec 08. 1-12
      The main biological function of the tumor suppressor p53 is to control cell cycle arrest and apoptosis. Among the p53 target genes, p21 has been identified as a key player in p53-mediated G1 arrest, while Killin, via its high DNA binding affinity, has been implicated in S and G2/M arrest. However, whether Killin is involved in G1 arrest remains unclear. This research aimed to explore the role of Killin in p53-mediated G1 arrest. Knockout of killin in human colorectal cells led to a dramatic decrease in p53-mediated G1 arrest upon DNA damage. Moreover, double knockout of killin and p21 completely abolished G1 arrest, similar to that of p53 knockout cells. We further showed that Killin could upregulate p21 protein expression independent of p53 via ubiquitination pathways. Immunoprecipitation studies indicated that Killin may directly bind to proteasome subunits, thereby disrupting proteasomal degradation of p21. Together, these results demonstrate that Killin is involved in multiple cell cycle checkpoint controls, including p53-mediated G1 arrest.
    Keywords:  G1 arrest; Killin; p21; p53; proteasome