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Journal article
Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma
Scientific reports, v 11(1), pp 3802-3802
15 Feb 2021
PMID: 33589694
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 (TGF beta 1). 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 TGF beta 1. 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 TGF beta 1-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.
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Details
- Title
- Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma
- Creators
- J. Alexander - Fox Chase Cancer CenterD. B. Vendramini-Costa - Fox Chase Cancer CenterR. Francescone - Fox Chase Cancer CenterT. Luong - Fox Chase Cancer CenterJ. Franco-Barraza - Fox Chase Cancer CenterN. Shah - Fox Chase Cancer CenterJ. C. Gardiner - Fox Chase Cancer CenterE. Nicolas - Fox Chase Cancer CenterK. S. Raghavan - Fox Chase Cancer CenterE. Cukierman - Fox Chase Cancer Center
- Publication Details
- Scientific reports, v 11(1), pp 3802-3802
- Publisher
- Springer Nature
- Number of pages
- 19
- Grant note
- R01 CA232256; R21 CA231252; T32CA009035; ACS -132561-PF-18-218-01-CSMA / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Worldwide Cancer Research Marianne Di Nofrio Pancreatic Research Foundation 5th AHEPA Cancer Research Foundation, Inc. Martin and Concetta Greenberg Pancreatic cancer Institute Pennsylvania's DOH Health Research Formula Funds
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Medicine (Graduate); Graduate School of Biomedical Sciences and Professional Studies
- Web of Science ID
- WOS:000623879500005
- Scopus ID
- 2-s2.0-85101451187
- Other Identifier
- 991019167940404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Multidisciplinary Sciences