Abstract
Pancreatic ductal adenocarcinoma (PDAC) claims ~93% of patient lives in less than 5 years proceeding diagnosis. Therapeutic options for PDAC are challenged by the deposition of a fibrous-like extracellular matrix (ECM) known as desmoplasia. This desmoplastic-ECM (D-ECM) forms the bulk of the tumor mass while remodeling the once tumor-suppressive microenvironment to become tumor permissive. Ironically, ablation of the D-ECM results in an even more aggressive PDAC. Thus, unraveling the mechanism of D-ECM induction is vital to reinstating the natural tumor-restrictive microenvironment of the pancreas. Although the underlying biology remains unclear, the D-ECM is initiated and maintained by activated cancer associated fibroblasts (CAFs). CAF activation is primarily driven by TGFβ1 signaling, which causes cytoskeletal rearrangements in support of CAF-dependent D-ECM onset. As such, the goal of this study is to define the cytoskeletal regulation needed to restore the natural tumor-suppressive properties of the pancreas. Therefore, we focused on the actin cross-linker palladin whose expression is regulated by TGFβ1 and has been identified as an independent prognostic marker for PDAC progression as well as CAF activation. We postulate palladin has an isoform-specific role in PDAC-associated desmoplasia that ultimately fuels cancer progression. Using an in vivo-mimetic 3D stroma model, I used a CRISPR/Cas9 approach to delete one or both of the major palladin isoforms in patient-derived CAFs and assessed CAF's activation via quantitative immunoblots, real-time polymerase chain reaction, and multiplex confocal microscopy in addition to palladin knockout CAF-derived ECM's ability to influence PDAC cell viability and invasive spread. My data indicate that palladin isoforms 3 and 4 are required for TGFβ1-depdendent CAF activation as well as for CAF-dependent D-ECM induction whereby knockdown of either isoform in CAFs results in a normalized ECM that restrains the inherent aggressive nature of PDAC cells. These findings suggest that targeting palladin alters the desmoplastic compartment by impeding tumor progression. Taken together, these results propose a strategy to restore a normal tumor-suppressive stroma in PDAC that will complement current PDAC treatment dogmas.
Citation Format: Jennifer Alexander, Edna Cukierman. Loss of cytoskeletal protein palladin desensitizes pancreatic cancer associated fibroblast to TGFβ1-dependent desmoplastic induction [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B070.
