Matrix-regulated integrin αvβ5 maintains α5 β1 -dependent desmoplastic traits prognostic of neoplastic recurrence

Janusz Franco-Barraza, Ralph Francescone, Tiffany Luong, Neelima Shah, Raj Madhani, Gil Cukierman, Essel Dulaimi, Karthik Devarajan, Brian L. Egleston, Emmanuelle Nicolas, R. Katherine Alpaugh, Ruchi Malik, Robert G. Uzzo, John P. Hoffman, Erica A. Golemis, Edna Cukierman

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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 αvβ1 -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.

Original languageEnglish
Article numbere20600
JournaleLife
Volume6
DOIs
StatePublished - Jan 31 2017

Keywords

  • Biomarkers, Tumor/analysis
  • Cancer-Associated Fibroblasts/chemistry
  • Carcinoma, Pancreatic Ductal/complications
  • Cell Membrane/chemistry
  • Extracellular Matrix/metabolism
  • Fibroma, Desmoplastic/complications
  • Humans
  • Integrin alpha5beta1/analysis
  • Transforming Growth Factor beta/metabolism

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