Stiffness-induced cancer-associated fibroblasts are responsible for immunosuppression in a PDGF ligand-dependent manner
Pancreatic ductal adenocarcinoma (PDAC) is associated with a vast stromal reaction that arises mainly from cancer-associated fibroblasts (CAFs) and promotes both immune escape and tumor growth. Here, we used a mouse model of KrasG12D mutation (KC) without or with deletion of the activin A receptor ALK4 (4KC), which strongly drives collagen deposition that leads to tissue stiffness. To understand this process, single cell transcriptomes were obtained from purified cancer associated fibroblasts (CAFs) and ductal tumor cells from KC and 4KC tissues. These analyses led to the identification of increased number of CAFs/Ducts receptor:ligand interactions under stiffness conditions and a population of stiffness-induced CAFs with a role in immunosuppression. Overall design: Single cell RNA sequencing was performed in FACS purified ductal tumor cells from a pool of five KC or 4KC mice (LSL-KrasG12D/+;Ptf1a-Cre mice).