Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a...

Area of Science:

• Gastroenterology
• Cancer Biology
• Developmental Biology

Background:

• Stromal fibroblasts regulate intestinal stem cells and signaling gradients.
• PDGFRA-expressing fibroblasts are implicated in early WNT-mediated tumorigenesis.

Purpose of the Study:

• To investigate the role of PDGFRA+ fibroblasts in WNT-driven intestinal oncogenesis.
• To identify signaling pathways mediating fibroblast-epithelial interactions during tumor initiation.

Main Methods:

• Single-cell RNA sequencing (RNA-seq) of mouse intestinal mesenchyme.
• Functional assays using organoids and a mouse model of WNT-driven oncogenesis.
• Analysis of CDX2 reduction in β-catenin mutant intestinal epithelium.

Main Results:

• PDGFRA+ fibroblasts reprogram to a fetal-like state during WNT oncogenesis.
• TGFβ signaling is induced in PDGFRA+ fibroblasts by oncogenic epithelium and sustains fetal-like organoid growth.
• Reduction of CDX2 accelerates WNT-dependent oncogenesis by promoting a fetal-like state.

Conclusions:

• PDGFRA+ fibroblasts are activated during WNT-driven intestinal oncogenesis.
• These activated fibroblasts promote a fetal-like epithelial state that precedes and facilitates tumor formation.
• Targeting fibroblast activation and TGFβ signaling may offer therapeutic strategies for WNT-driven intestinal tumors.