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 TGFβ to drive gemcitabine resistance. Finally, we report that ITGA1 is required for TGFβ/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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / diagnosis
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Aldehyde Dehydrogenase 1 Family
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Animals
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Antimetabolites, Antineoplastic / pharmacology
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Biomarkers, Tumor / antagonists & inhibitors
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Chick Embryo
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Chorioallantoic Membrane / blood supply
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Chorioallantoic Membrane / drug effects
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Collagen / genetics
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Collagen / metabolism
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Resistance, Neoplasm / genetics*
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Epithelial-Mesenchymal Transition
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Gemcitabine
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Gene Expression Regulation, Neoplastic*
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Humans
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Integrin alpha Chains / antagonists & inhibitors
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Integrin alpha Chains / genetics*
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Integrin alpha Chains / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Pancreatic Neoplasms / diagnosis
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Prognosis
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Retinal Dehydrogenase / genetics
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Retinal Dehydrogenase / metabolism
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Signal Transduction
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Tissue Array Analysis
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Transforming Growth Factor beta / pharmacology
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Tumor Microenvironment / genetics
Substances
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Antimetabolites, Antineoplastic
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Biomarkers, Tumor
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Integrin alpha Chains
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Isoenzymes
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RNA, Small Interfering
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Transforming Growth Factor beta
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integrin alpha 10
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Deoxycytidine
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Collagen
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Aldehyde Dehydrogenase 1 Family
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ALDH1A1 protein, human
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Retinal Dehydrogenase
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Gemcitabine