bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021‒11‒21
ten papers selected by
Maria-Virginia Giolito

  1. Nat Commun. 2021 Nov 18. 12(1): 6741
      Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.
  2. JCI Insight. 2021 Nov 16. pii: e151815. [Epub ahead of print]
      Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial glucocorticoid receptor (GR), but not whole intestinal tissue GR, promotes chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In colorectal cancer patients, GR is enriched in intestinal epithelial cells and high epithelial GR is associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increases macrophage infiltration, improves tissue recovery, and enhances anti-tumor response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice develop fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early-phase of tissue injury delays recovery and accelerates the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling represses acute colitis but promotes chronic inflammation-associated colorectal cancer, and suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that although synthetic glucocorticoid treatment for IBD should be used with caution, there is a therapeutic window for glucocorticoid therapy during colorectal cancer development in immunocompetent patients.
    Keywords:  Colorectal cancer; Gastroenterology; Inflammatory bowel disease; Innate immunity; Oncology
  3. Cell Mol Gastroenterol Hepatol. 2021 Nov 12. pii: S2352-345X(21)00237-X. [Epub ahead of print]
      BACKGROUND AND AIMS: We previously demonstrated that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells.METHODS: Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of four histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type (WT) and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium (DSS)-induced colitis.
    RESULTS: Data analysis of RNA sequencing and quantitative reverse transcription-PCR (qRT-PCR) revealed that Hrh2 (H2R gene) is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded pro-inflammatory features via NF-kB and MAPK signaling pathways, and suppressed T cell proliferation. On the other hand, low-density neutrophils (LDNs) which totally lack H2R activation displayed an immature phenotype compared to WT LDNs, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4 (TLR4).
    CONCLUSION: Blocking H2R signaling enhanced pro-inflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis.
    Keywords:  cimetidine; colorectal cancer; histamine; inflammation
  4. J Oncol. 2021 ;2021 9355555
      Increasing evidence indicates that nuclear factor, erythroid 2-like 3 (Nrf3) is connected with tumorigenesis. However, the relationship between Nrf3 and tumor drug resistance remains elusive. In this study, we investigated the effect and mechanism of action by which Nrf3 regulated the sensitivity of colon cancer cells to 5-fluorouracil (5-FU). We found Nrf3 was significantly increased in colon cancer tissues. Furthermore, we observed that Nrf3 knockdown and overexpression can significantly affect the sensitivity of colon cancer cells to 5-FU in vitro and in vivo. Moreover, Nrf3 promoted the expression of RELA, P-RELA, and BCL-2. Inhibition of NF-κB partly reversed the effects of Nrf3 overexpression, resulting in the resistance of colon cancer cells to 5-FU. Overall, the study revealed that Nrf3 was connected to the sensitivity of colon cancer cells to 5-FU, and its possible mechanism was related to the NF-κB signaling pathway, which provided a new target for overcoming the resistance of colon cancer cells to 5-FU.
  5. Nat Commun. 2021 Nov 17. 12(1): 6654
      In current clinical practice, tumor response assessment is usually based on tumor size change on serial computerized tomography (CT) scan images. However, evaluation of tumor response to anti-vascular endothelial growth factor therapies in metastatic colorectal cancer (mCRC) is limited because morphological change in tumor may occur earlier than tumor size change. Here we present an analysis utilizing a deep learning (DL) network to characterize tumor morphological change for response assessment in mCRC patients. We retrospectively analyzed 1,028 mCRC patients who were prospectively included in the VELOUR trial (NCT00561470). We found that DL network was able to predict early on-treatment response in mCRC and showed better performance than its size-based counterpart with C-Index: 0.649 (95% CI: 0.619,0.679) vs. 0.627 (95% CI: 0.567,0.638), p = 0.009, z-test. The integration of DL network with size-based methodology could further improve the prediction performance to C-Index: 0.694 (95% CI: 0.661,0.720), which was superior to size/DL-based-only models (all p < 0.001, z-test). Our study suggests that DL network could provide a noninvasive mean for quantitative and comprehensive characterization of tumor morphological change, which may potentially benefit personalized early on-treatment decision making.
  6. Nat Mater. 2021 Nov 15.
      Epithelial organoids are most efficiently grown from mouse-tumour-derived, reconstituted extracellular matrix hydrogels, whose poorly defined composition, batch-to-batch variability and immunogenicity limit clinical applications. Efforts to replace such ill-defined matrices for organoid culture have largely focused on non-adaptable hydrogels composed of covalently crosslinked hydrophilic macromolecules. However, the excessive forces caused by tissue expansion in such elastic gels severely restrict organoid growth and morphogenesis. Chemical or enzymatic degradation schemes can partially alleviate this problem, but due to their irreversibility, long-term applicability is limited. Here we report a family of synthetic hydrogels that promote extensive organoid morphogenesis through dynamic rearrangements mediated by reversible hydrogen bonding. These tunable matrices are stress relaxing and thus promote efficient crypt budding in intestinal stem-cell epithelia through increased symmetry breaking and Paneth cell formation dependent on yes-associated protein 1. As such, these well-defined gels provide promising versatile matrices for fostering elaborate in vitro morphogenesis.
  7. Nat Commun. 2021 Nov 18. 12(1): 6711
      Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.
  8. Front Pharmacol. 2021 ;12 739501
      SHP2 mediates signaling from multiple receptor tyrosine kinases (RTKs) to extracellular signal-regulated kinase (ERK) and Ser and Thr kinase AKT, and its inhibitors offer an unprecedented opportunity for cancer treatment. Although the ERK signaling variation after SHP2 inhibition has been well investigated, the AKT signaling variation in colorectal carcinoma (CRC) is still unknown. Therefore, we performed immunohistochemistry and bioinformatics analyses to explore the significance of p-SHP2 in CRC. A panel of CRC cell lines with the SHP2 inhibitor, SHP099, was used to assess the effects on viability and signaling. The inhibitors of AKT and focal adhesion kinase (FAK) signaling were examined in combination with SHP099 as potential strategies to enhance the efficacy and overcome resistance. Frequent resistance to the SHP2 inhibitor was observed in CRC cells, even in those without RAS mutations. We observed rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition, possibly driven by the reactivation of RTKs or released p-FAK. High baseline p-FAK may also be associated with CRC cell resistance to SHP2 inhibition. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition. Moreover, the combined inhibition of SHP2 with AKT or FAK resulted in sustained AKT pathway suppression and improved antitumor efficacy in vitro and in vivo. Our study found that reactivation of the AKT pathway is a key mechanism of adaptive resistance to SHP2 inhibition, highlighting the potential significance of AKT and FAK inhibition strategies to enhance the efficacy of SHP2 inhibitors in CRC treatment.
    Keywords:  AKT rebound; FAK; SHP2; colorectal carcinoma; drug resistance
  9. Future Oncol. 2021 Nov 15.
      Oxaliplatin-based chemotherapy with a regimen such as FOLFOX with or without targeted therapy is a standard of care option for advanced colorectal cancer; however, long-term exposure to oxaliplatin is associated with cumulative toxicity. Growing evidence suggests maintenance therapy with a less intensive regimen after platinum-based induction therapy can provide continuing benefit with reduced toxicity. We describe the rationale and design of the Phase III LYNK-003 trial, which will evaluate the efficacy and safety of olaparib with or without bevacizumab compared with 5-fluoruracil plus bevacizumab in patients with unresectable or metastatic colorectal cancer that has not progressed on an induction course of FOLFOX plus bevacizumab. The primary end point is progression-free survival by independent central review; secondary end points include overall survival, objective response, duration of response and safety. Clinical trial registration: NCT04456699.
    Keywords:  5-fluorouracil; FOLFOX; PARP inhibitor; bevacizumab; colorectal cancer; folinic acid; irinotecan; maintenance therapy; olaparib; oxaliplatin