Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through SFRP4 Signaling.

Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis. To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells. Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix (ECM) gene expression in ASC. We investigated the function of two markers of the fibroblastic transition highly induced by cancer cells: a long non-coding RNA and a Wnt signaling modulator . By using ASCs with either or knocked out (ko), we showed that both genes are required for Wnt/TGFβ signaling and ECM induction in ASCs by Capan-1. Analysis of changes in Capan-1 genes that rely on and expression in ASCs also identified the Wnt and TGF pathways. ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis. We conclude that promotes cancer progression in pancreatic cancer and is a promising therapeutic target.