Loss of mismatch repair signaling impairs the WNT–bone morphogenetic protein crosstalk and the colonic homeostasis

Abstract

<jats:title>Abstract</jats:title> <jats:p>The fine balance between proliferation, differentiation, and apoptosis in the colonic epithelium is tightly controlled by the interplay between WNT, Notch, and bone morphogenetic protein (BMP) signaling. How these complex networks coordinate the colonic homeostasis, especially if cancer predisposing mutations such as mutations in the DNA mismatch repair (MMR) are present, is unclear. Inactivation of the MMR system has long been linked to colorectal cancer; however, little is known about its role in the regulation of the colonic homeostasis. It has been shown that loss of MMR promotes the proliferation of colon epithelial cells that renders them highly susceptible to transformation. The mechanism through which MMR mediates this effect, yet, remains to be determined. Using an MMR-deficient mouse model, we show that increased methylation of Dickkopf1 impacts its expression, and consequently, the ability to negatively regulate WNT signaling. As a result, excessive levels of active β-catenin promote strong crypt progenitor-like phenotype and abnormal proliferation. Under these settings, the development and function of the goblet cells are affected. MMR-deficient mice have fewer goblet cells with enlarged mucin-loaded vesicles. We further show that MMR inactivation impacts the WNT–BMP signaling crosstalk.</jats:p>

Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer

“…According to Norgaard et al , mutation of MSH2 leads to hypermethylation of the DKK1 promoter, 43 resulting in DKK1 inhibition. Moreover, sporadic dMMR CRCs are strongly correlated with the hypermethylated MLH1 promoter and BRAF V600E , 44 which do not influence DKK1 expression.…”

Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation

“…The question of why MMR-deficient tumors preferentially arise in the colon can be at least partially answered by its regulatory function in the differentiation of colon crypt stem cells and progenitor cells into epithelial cells [ 139 ]. The homeostasis of colon stem cells and their differentiated progeny is tightly regulated via the integration of signals from Notch, bone-morphogenic protein (BMP), and WNT/ß-catenin signaling [ 140 ].…”

“…A recent study revealed that MMR deficiency causes hypermethylation of CpG regions in the Dickkopf 1 (DKK1) gene, which is an antagonist of Wnt signaling [ 139 ]. Loss of DKK1 function in epithelial cells of the colon crypts (colon epithelial cells, CECs) leads to enhanced WNT/ß-catenin signaling, thus promoting the stemness phenotype and uncontrolled proliferation.…”

“…Loss of DKK1 function in epithelial cells of the colon crypts (colon epithelial cells, CECs) leads to enhanced WNT/ß-catenin signaling, thus promoting the stemness phenotype and uncontrolled proliferation. Interestingly, because of MMR deficiency, BMP signaling was also up-regulated in the CECs [ 139 ]. Therefore, the authors concluded that alterations in the WNT/ß-catenin and BMP signaling in CECs with dysfunctional MMR disturbs the tightly regulated homeostasis of the stem, progenitor, and differentiated cells [ 139 ].…”

“…Interestingly, because of MMR deficiency, BMP signaling was also up-regulated in the CECs [ 139 ]. Therefore, the authors concluded that alterations in the WNT/ß-catenin and BMP signaling in CECs with dysfunctional MMR disturbs the tightly regulated homeostasis of the stem, progenitor, and differentiated cells [ 139 ]. These findings suggest that targeting WNT/ß-catenin signaling could at least in part counteract the transformative effect of MMR deficiency.…”