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Matrix-regulated integrin alphavbeta5 maintains alpha5beta1-dependent desmoplastic traits prognostic of neoplastic recurrence
Elife. 2017 Jan 31;6
PMID: 28139197    PMCID: PMC5283834    URL: https://www.ncbi.nlm.nih.gov/pubmed/28139197
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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 alpha5beta1-integrin. Mechanistically, we established that TGFbeta is required for D-ECM production but dispensable for D-ECM-induced naive fibroblast-to-CAF activation, which depends on alphavbeta5-integrin redistribution of pFAK-independent active alpha5beta1-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 alpha5beta1-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool.
2050-084x Franco-Barraza, Janusz ORCID: http://orcid.org/0000-0003-3652-5311 Francescone, Ralph Luong, Tiffany Shah, Neelima Madhani, Raj Cukierman, Gil Dulaimi, Essel Devarajan, Karthik Egleston, Brian L Nicolas, Emmanuelle Katherine Alpaugh, R Malik, Ruchi Uzzo, Robert G Hoffman, John P Golemis, Erica A Cukierman, Edna ORCID: http://orcid.org/0000-0002-1452-9576 Journal Article England Elife. 2017 Jan 31;6. pii: e20600. doi: 10.7554/eLife.20600.