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.
Highlights
While pancreatic cancer research efforts and the tools with which to study this malignancy have increased drastically over the past few decades, the 5-year survival rate remains at only 7% and the median survival from the time of diagnosis is less than 12 months[1,2,3]
Since mesenchymal cell morphology and gene expression signatures are commonly associated with the metastatic potential of pancreatic cancer cells, we evaluated whether collagen could affect the morphology, spreading and attachment of Pancreatic ductal adenocarcinoma (PDAC) cells in an integrin alpha 1 (ITGA1)-dependent manner
Three precursor lesion types have been carefully characterized in the pancreas of patients with and without ductal adenocarcinomas [i.e., intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs)]
Summary
While pancreatic cancer (pancreatic ductal adenocarcinoma or PDAC) research efforts and the tools with which to study this malignancy have increased drastically over the past few decades, the 5-year survival rate remains at only 7% and the median survival from the time of diagnosis is less than 12 months[1,2,3]. This is due primarily to the heterogeneity of the highly desmoplastic tumor microenvironment[7] To combat this cellular and molecular complexity, and improve therapy responses at both primary and metastatic tumor sites, it has become apparent that future therapeutic approaches will need to target the interaction between rare stem-like cancer cells and their tumor-protective environment[8,9,10]. In this regard, we mined our previously published peudopodium proteomic data for proteins frequently upregulated in PDAC and that regulate cell-extracellular interactions. This work provides rationale for using ITGA1 as a diagnostic biomarker and therapeutic target to improve patient survival
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