Files and links (1)
PDFOpen Access (License Unspecified), Open Access
Dissertation
Palladin isoforms regulate the functional heterogeneity of cancer associated fibroblast in pancreatic ductal adenocarcinoma
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2019
DOI:
https://doi.org/10.17918/pge7-zc44
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating malignancy with a five-year survival of ~9%. Treatment of PDAC is compromised partly due to excessive, fibrotic-like, stromal remodeling known as desmoplasia. Desmoplasia limits therapeutic perfusion, supports tumor growth and survival, and assists in establishing an immunosuppressive microenvironment. These processes are primarily regulated by TGF[beta]1 and [alpha]v[beta]5-integrin induced cancer-associated fibroblast (CAF) activation. Paradoxically, ablation of CAFs can result in a more aggressive disease, suggesting CAFs could also restrain tumors. Thus, unraveling the mechanism(s) underlying the tumor promoting vs restricting functions of CAFs could lead to therapies that promote natural tumor-suppressive functions of the stroma. CAF activation is facilitated by cytoskeletal rearrangements, some of which are mediated by the f-actin organizing protein palladin. Stromal palladin expression correlates with disease onset and progression. Palladin includes 9 isoforms, yet isoforms 3 and 4 (iso3/4) are specifically up-regulated during TGF[beta]1-induced CAF activation. However, the role of iso3 and iso4 in CAF activation and function remain elusive. Using a CAF-derived desmoplastic extracellular matrix (ECM) model, we found that CAFs depend on both palladin isoforms to sustain TGF[beta]1 signaling, whereas other CAF functions are regulated by only one of these isoforms. Specifically, iso3 promotes the secretion of pro-tumor cytokines IL-6 and IL-8 in cells that lack [alpha]v[beta]5-integrin, while iso4 regulates [alpha]SMA expression and stress fiber localization as well as fibronectin orientation. Additionally, loss of either isoform alters desmoplastic ECM remodeling such that iso3 and iso4 null CAF-derived ECMs fail to support cancer cell growth. Taken together, these findings demonstrate a novel role of palladin in CAF biology and suggests that iso3 and iso4 promote specific tumor-supportive CAF roles. Furthermore, this study highlights the therapeutic potential of restoring the natural anti-tumor activity of the pancreatic microenvironment.
Metrics
166 File views/ downloads
48 Record Views
Details
- Title
- Palladin isoforms regulate the functional heterogeneity of cancer associated fibroblast in pancreatic ductal adenocarcinoma
- Creators
- Jennifer Imena Alexander - DU
- Contributors
- Edna Cukierman (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 166 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Drexel University
- Other Identifier
- 9641; 991014632056404721