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Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G, Dulaimi E, Devarajan K, Egleston BL, Nicolas E, Katherine Alpaugh R, Malik R, Uzzo RG, Hoffman JP, Golemis EA, Cukierman E
Matrix-regulated integrin alphavbeta5 maintains alpha5beta1-dependent desmoplastic traits prognostic of neoplastic recurrence
Elife (2017) In process.
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 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.
Note
Publication Date: 2017-01-31.
PMCID: PMC5283834
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Last updated on Tuesday, December 04, 2018