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

<b>Background/objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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 <i>LINC01614</i> and a Wnt signaling modulator <i>SFRP4</i>. By using ASCs with either <i>SFRP4</i> or <i>LINC01614</i> 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 <i>LINC01614</i> and <i>SFRP4</i> expression in ASCs also identified the Wnt and TGF pathways. <i>SFRP4</i> ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in <i>SFRP4</i> ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis. <b>Conclusions:</b> We conclude that <i>SFRP4</i> promotes cancer progression in pancreatic cancer and is a promising therapeutic target.