Projected unfavorable tumor biology by extracellular matrix-receptor at the premalignant stage of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinctive molecular subtypes in cancer cells and the tumor microenvironment (also known as stroma subtype). In a mouse model of inflammation-accelerated KrasG12D-driven PDAC, we identified a transcriptional signature of extracellular matrix (ECM)-receptor, persistently altered in pancreatic pre-neoplastic lesions. This ECM-receptor signature is particularly enriched for ECM structure proteins and subunits of integrin subfamily. Further analysis revealed that cancer cells, cancer-associated fibroblasts (CAFs), and macrophages contributed to the ECM-receptor signature. Notably, the signature-enriched human tumors tended to be the basal-like/squamous subtype associated with poor prognosis. Thus, it argues for projected unfavorable tumor biology by ECM-receptor at the pre-neoplastic stage of pancreatic carcinogenesis. It is noteworthy that this ECM-receptor signature negatively selects PDAC patients with immunogenic subtype, who may benefit from upcoming immunotherapy.