Jahangir Iqbal

Wnt-mediated tissue transformation is more pronounced in the small intestine and is associated with activation of regenerative pathways

Modification of Epiregulin levels in mesenchyme or enteroids does not impact growth or viability of either control or β-cateninGOF enteroids

Decreased levels of CDX2 enhances the fetal state via YAP activation

Reprogramming of Pdgfra+ fibroblasts in β-cateninGOF mice

Pdgfra cells are responsive to TGFB1 that acts as a strong inducer of fetal and regenerative genes in the epithelium

Increased expression of both pro-regenerative and Wnt signaling antagonists occur in Pdgfra-lo cells exposed to oncogenic epithelium

Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt–villus axis in the intestine and provide a niche that supports intestinal stem cells. In this study, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing of mesenchymal cell populations revealed a dynamic reprogramming of PDGFRA+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain the fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation.Significance:TGFβ signaling activated in PDGFRA+ fibroblasts in response to the initial transformation of WNT-hyperactive epithelial cells mediates expression of pro-regeneration ligands that reciprocally induce a fetal-like state in the epithelium, facilitating tumorigenesis.

Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt–villus axis in the intestine and provide a niche that supports intestinal stem cells. In this study, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing of mesenchymal cell populations revealed a dynamic reprogramming of PDGFRA+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain the fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation. Significance: TGFβ signaling activated in PDGFRA+ fibroblasts in response to the initial transformation of WNT-hyperactive epithelial cells mediates expression of pro-regeneration ligands that reciprocally induce a fetal-like state in the epithelium, facilitating tumorigenesis.