H. Lindsay1, D. Foster1, M. Griffin1, J. Parker1, D. Delitto1, M. Longaker1, J. Norton1 1Stanford University, Department Of Surgery, Palo Alto, CA, USA
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with significant desmoplasia that limits immune and chemotherapy efficacy. Desmoplasia is caused by cancer associated fibroblasts (CAFs) that secrete collagen which cross link and result in a dense fibrous network. CAFs are the most populous cell type in PDAC and are an appealing target to improve anti-PDAC therapy. The purpose of this study is to identify targets to use for anti-CAF therapy to treat pancreatic ductal adenocarcinoma PDAC.
Methods:
To develop a murine model for PDAC the body of the pancreas was ligated and 25-50K KPC PDAC tumor cells were injected into the tail of the pancreas in C57 BL/6 mice. At 3 weeks post-injection, the tumor was harvested and fixed. The fixed tumor was embedded, sectioned, and stained using double antibody immunofluorescent (IF) staining.
Results:
IF histology for Col-1 and α-SMA identified activated fibroblasts at the periphery of the tumor (not shown). IF demonstrated upregulated CAF markers of therapeutic interest; Fibroblast activation protein (FAP) (Figure 1, A and B), Peptidyl-prolyl cis/trans isomerase (Pin-1) (Figure 1, C and D), and interleukin-1 receptor (IL-1R) (Figure 1, G and H) had the most significant increased expression compared to non-specific binding control.
Conclusion:
The murine PDAC tumor shows prominent CAF expression suggesting excellent fibroblast recruitment and activation. IL-1R, Pin-1, and FAP, all potential targets for anti-CAF tumor therapies, are expressed near the surface of the tumor mimicking human PDAC. This model closely mimics human PDAC and will allow for analysis of in vivo anti-CAF PDAC treatments.
