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:

• Pancreatic cancer
• perlecan
• CAFs
• fibroblasts
• imaging
• NFκB
• stroma

Declaration of interest

S Ritchie is supported by a University of New South Wales (UNSW) International Postgraduate Award. C Vennin is supported by a Human Frontier Science Program (HFSP) Fellowship. P Timpson is supported by the Len Ainsworth Fellowship in Pancreatic Cancer Research and is a National Health and Medical Research Council (NHMRC) Senior Research Fellow. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by Suttons, Sydney Catalyst, NHMRC, Cancer Council NSW, Cancer Institute NSW. This work was also made possible by an Avner Pancreatic Cancer Foundation.