Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal 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.