Targeting genetically-tuned CAFs in pancreatic cancer via perlecan manipulation

Abstract

Introduction: Pancreatic cancer (PC) is responsible for significant worldwide cancer-associated mortality and has one of the lowest five-year survival rate post-diagnosis of all epithelial cancers. A major contributor to this dismal outcome is the extensive stromal reaction that occurs during PC progression. As such, targeting key components of the pancreatic tumor stroma in combination with standard-of-care chemotherapy has been a recent focus in both the pre-clinical and clinical settings.Areas Covered: In this commentary, we highlight how perlecan was identified as a new potential target for this disease.Expert Opinion: Perlecan is deposited by cancer-associated fibroblasts (CAFs) in the pancreatic tumor stroma, and work from our laboratory group recently demonstrated that depleting perlecan reduces metastatic spread, while also improving chemotherapy efficacy in pancreatic tumors harboring a gain-of-function p53 mutation. We also discuss potential strategies to therapeutically target perlecan which could be tested in pre-clinical models prior to translation into the clinic.

Keywords: CAFs; NFκB; Pancreatic cancer; fibroblasts; imaging; perlecan; stroma.