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Sci Rep ; 7(1): 10060, 2017 08 30.
Article in English | MEDLINE | ID: mdl-28855593

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has single-digit 5-year survival rates at <7%. There is a dire need to improve pre-malignant detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that integrin alpha 1 (ITGA1) is frequently upregulated in pancreatic cancers and associated precursor lesions. Expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis, and depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced tumorigenic potential. Notably, collagen/ITGA1 signaling promotes the survival of ALDH1-positive stem-like cells and cooperates with TGFß to drive gemcitabine resistance. Finally, we report that ITGA1 is required for TGFß/collagen-induced EMT and metastasis. Our data suggest that ITGA1 is a new diagnostic biomarker and target that can be leveraged to improve patient outcomes.


Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Integrin alpha Chains/genetics , Pancreatic Neoplasms/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Aldehyde Dehydrogenase 1 Family , Animals , Antimetabolites, Antineoplastic/pharmacology , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Chick Embryo , Chorioallantoic Membrane/blood supply , Chorioallantoic Membrane/drug effects , Collagen/genetics , Collagen/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Epithelial-Mesenchymal Transition , Humans , Integrin alpha Chains/antagonists & inhibitors , Integrin alpha Chains/metabolism , Isoenzymes/genetics , Isoenzymes/metabolism , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Prognosis , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Retinal Dehydrogenase/genetics , Retinal Dehydrogenase/metabolism , Signal Transduction , Tissue Array Analysis , Transforming Growth Factor beta/pharmacology , Tumor Microenvironment/genetics , Gemcitabine
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