Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence
Abstract
Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active α5β1-integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on αvβ5-integrin redistribution of pFAK-independent active α5β1-integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and α5β1-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 31, 2017
- Source ID
- 10.7554/elife.20600
Entities
People
- Brian L. Egleston
- Edna Cukierman
- Emmanuelle Nicolas
- Erica Golemis
- Essel Dulaimi
- Gil Cukierman
- Janusz Franco-Barraza
- John P Hoffman
- Karthik Devarajan
- Neelima Shah
- R. Katherine Alpaugh
- Raj Madhani
- Ralph Francescone
- Robert G. Uzzo
- Ruchi Malik
- Tiffany Luong
Organizations
- Fox Chase Cancer Center
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense