Adipose stromal cell-derived cancer-associated fibroblasts promote pancreatic adenocarcinoma 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 ASC 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 LINC01614 and a Wnt signaling modulator SFRP4. By using ASC with either SFRP4 or LINC01614 knocked out (ko), we showed that both genes are required for Wnt / TGFβ signaling and ECM induction in ASCs by Capan1. Analysis of changes in Capan-1 genes that rely on LINC01614 and SFRP4 expression in ASC also identified the Wnt and TGF pathways. SFRP4 ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in SFRP4 ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis. We conclude that SFRP4 promotes cancer progression in pancreatic cancer and is a promising therapeutic target.