bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021‒11‒14
four papers selected by
Maria-Virginia Giolito

  1. Am J Physiol Gastrointest Liver Physiol. 2021 Nov 10.
      IL22 signaling plays an important role in maintaining gastrointestinal epithelial barrier function, cell proliferation and protection of intestinal stem cells from genotoxicants. Emerging studies indicate that the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, promotes production of IL22 in gut immune cells. However, it remains to be determined if AhR signaling can also affect the responsiveness of colonic epithelial cells to IL22. Here, we show that IL22 treatment induces the phosphorylation of STAT3, inhibits colonic organoid growth, and promotes colonic cell proliferation in vivo. Notably, intestinal cell specific AhR knockout (KO) reduces responsiveness to IL22 and compromises DNA damage response following exposure to carcinogen, in part due to the enhancement of SOCS3 expression. Deletion of SOCS3 increases levels of pSTAT3 in AhR KO organoids, and phenocopies the effects of IL22 treatment on wildtype (WT) organoid growth. In addition, pSTAT3 levels are inversely associated with increased AOM/DSS induced colon tumorigenesis in AhR KO mice. These findings indicate that AhR function is required for optimal IL22 signaling in colonic epithelial cells and provide rationale for targeting AhR as a means of reducing colon cancer risk.
    Keywords:  IL22 signaling; SOCS3; aryl hydrocarbon receptor; colonic epithelial cells
  2. Mol Cancer Res. 2021 Nov 09. pii: molcanres.0224.2021. [Epub ahead of print]
      Regenerating Gene 4 (Reg4) is highly upregulated in gastrointestinal (GI) malignancies including colorectal and pancreatic cancers. Numerous studies demonstrated an association between higher Reg4 expression and tumor aggressiveness, intrinsic resistance to apoptotic death, and poor outcomes from GI malignancies. However, the precise receptor and underlying signaling mechanism have remained unknown. Although we previously reported a Reg4-mediated induction of epidermal growth factor receptor (EGFR) activity in colorectal cancer (CRC) cells, a direct interaction between Reg4 and EGFR was not observed. The present study is focused on identifying the cell surface binding partner of Reg4 and dissecting its role in CRC and pancreatic cancer (PC) growth and stem cell survival. In vitro models of human CRC and PC were used to evaluate the results. Results of this study find: i) Reg4 interacts with CD44, a transmembrane protein expressed by a population of CRC and PC cells, ii) Reg4 activates regulated intramembrane proteolysis (RIP) of CD44 resulting in γ-Secretase-mediated cleavage and release of the CD44 intracytoplasmic domain (CD44ICD) that functions as a transcriptional activator of D-type cyclins involved in the regulation of cancer cell proliferation and Klf4 and Sox2 expression involved in regulating pluripotency of cancer stem cells; and iii) Reg4 significantly increases CRC and PC cell proliferation and their clonogenic potential in stem cell assays. Implications: These results suggest that pro-proliferative and pro-stemness effects of Reg4 are mediated through γ-Secretase-mediated CD44/CD44ICD signaling, hence strategies to disrupt Reg4-CD44-γ-Secretase-CD44ICD signaling axis may increase cancer cell susceptibility to chemo and radiotherapeutics.
  3. Development. 2021 Nov 01. pii: dev199683. [Epub ahead of print]148(21):
      Although the role of the transcription factor NF-κB in intestinal inflammation and tumor formation has been investigated extensively, a physiological function of NF-κB in sustaining intestinal epithelial homeostasis beyond inflammation has not been demonstrated. Using NF-κB reporter mice, we detected strong NF-κB activity in Paneth cells, in '+4/+5' secretory progenitors and in scattered Lgr5+ crypt base columnar stem cells of small intestinal (SI) crypts. To examine NF-κB functions in SI epithelial self-renewal, mice or SI crypt organoids ('mini-guts') with ubiquitously suppressed NF-κB activity were used. We show that NF-κB activity is dispensable for maintaining SI epithelial proliferation, but is essential for ex vivo organoid growth. Furthermore, we demonstrate a dramatic reduction of Paneth cells in the absence of NF-κB activity, concomitant with a significant increase in goblet cells and immature intermediate cells. This indicates that NF-κB is required for proper Paneth versus goblet cell differentiation and for SI epithelial homeostasis, which occurs via regulation of Wnt signaling and Sox9 expression downstream of NF-κB. The current study thus presents evidence for an important role for NF-κB in intestinal epithelial self-renewal.
    Keywords:  Epithelial self-renewal; Goblet cells; Intestine; Mouse; NF-κB; Paneth cells; Stem cells
  4. Cell Death Differ. 2021 Nov 09.
      Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.