title: Matrix-regulated integrin αvβ5maintains 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.
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Janusz
authors.identifier: 0000-0003-3652-5311
authors.initials: J
authors.lastname: Franco-Barraza
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Francescone
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Luong
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Neelima
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Raj
authors.initials: R
authors.lastname: Madhani
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Gil
authors.initials: G
authors.lastname: Cukierman
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Essel
authors.initials: E
authors.lastname: Dulaimi
authors.affiliation: Department of Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Department of Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Egleston
authors.affiliation: Programs in Genomics, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.affiliation: Protocol Support Lab, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: R
authors.initials: R
authors.lastname: Katherine Alpaugh
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Malik
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.|Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Uzzo
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Hoffman
authors.affiliation: Department of Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
authors.affiliation: Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
authors.forename: Edna
authors.identifier: 0000-0002-1452-9576
authors.initials: E
authors.lastname: Cukierman
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D000072645:Cancer-Associated Fibroblasts / Q000737:chemistry*; D021441:Carcinoma, Pancreatic Ductal / Q000150:complications* / Q000473:pathology*; D002462:Cell Membrane / Q000737:chemistry*; D005109:Extracellular Matrix / Q000378:metabolism; D018220:Fibroma, Desmoplastic / Q000150:complications* / Q000473:pathology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000032:analysis*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D039081:Integrin alpha5beta1; D016212:Transforming Growth Factor beta
keywords: alpha5beta1 integrin; alphavbeta5 integrin; cancer biology; cancer-associated fibroblasts; desmoplasia; extracellular matrix; human; human biology; medicine; mouse; myofibroblasts; pancreatic ductal adenocarcinoma