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.
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.
MeSH terms
alpha5beta1 integrin alphavbeta5 integrin cancer-associated fibroblasts desmoplasia extracellular matrix human biology medicine mouse myofibroblasts pancreatic ductal adenocarcinoma human cancer biology
alpha5beta1 integrin alphavbeta5 integrin cancer-associated fibroblasts desmoplasia extracellular matrix human biology medicine mouse myofibroblasts pancreatic ductal adenocarcinoma human cancer biology
Note
Publication Date: 2017-01-31.
Publication Date: 2017-01-31.