Abstract LB-149: ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of few malignancies to have single-digit 5-year survival rates at <7%. This dismal prognosis is due in part to the limited ability of clinicians to make pre-metastatic diagnoses and effectively treat localized pancreatic tumors. Thus, there is a dire need to improve early 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 37 of the top 100 PDE proteins are frequently upregulated in human pancreatic cancer and other tumor types. Integrin alpha 1 (ITGA1) was of primary interest because its high expression in pancreatic cancer precursor lesions may provide a path toward earlier diagnoses, while targeting its cell surface function may abrogate tumor-stroma interactions known to exacerbate PDAC. In this regard, the expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis such as high tumor grade, p53/SMAD4 mutation status and erlotinib resistance. Depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced migration and survival. We further demonstrate that collagen induces PDAC cell attachment and spreading in an ITGA1-dependent manner. 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 increased ITGA1 expression in PDAC tissue indicates the presence of epithelial-mesenchymal transition (EMT) and that ITGA1 is required for TGFβ/collagen-induced EMT and hepatotropic metastasis. Our data suggest that ITGA1 is a new biomarker for PDAC initiation and, when targeted, can sensitize tumors to available chemotherapies to suppress the growth of pancreatic tumors at primary and metastatic sites. Citation Format: Sa La Kim, Armen Gharibi, Justin Molnar, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Julie Hong, Jonathan A. Kelber. ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-149. doi:10.1158/1538-7445.AM2017-LB-149