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Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma
Sci Rep. 2021 Feb 15;11(1) :3802
PMID: 33589694    PMCID: PMC7884442   
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Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.
Notes
2045-2322 Alexander, J I Vendramini-Costa, D B Francescone, R Luong, T Franco-Barraza, J Shah, N Gardiner, J C Nicolas, E Raghavan, K S Cukierman, E Orcid: 0000-0002-1452-9576 R21 CA231252/CA/NCI NIH HHS/United States S10 OD023666/OD/NIH HHS/United States 20-0081/AICR_/Worldwide Cancer Research/United Kingdom R01 CA232256/CA/NCI NIH HHS/United States T32 CA009035/CA/NCI NIH HHS/United States CA06927/Foundation for the National Institutes of Health/ T32CA009035/NIH/NCI T32 Training Grant/ 132561-PF-18-218-01-CSMA/American Cancer Society/ P30 CA006927/CA/NCI NIH HHS/United States Journal Article Sci Rep. 2021 Feb 15;11(1):3802. doi: 10.1038/s41598-021-82937-3.