RNA expression patterns in pancreatic intraepithelial neoplasia
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Date
2016-11-04
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Johns Hopkins University
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a genetic disease that evolves from precursor lesions, the most common of which are pancreatic intraepithelial neoplasia (PanINs). In this study, we present RNA-sequencing analysis of PanINs. We identify genes subject to differential expression between PanIN and normal pancreatic duct and between low-grade and high-grade PanIN. One novel gene identified as overexpressed in PanIN and invasive pancreatic ductal adenocarcinoma is interleukin-2 receptor subunit gamma (IL2RG) which encodes the common gamma chain. CRISPR-mediated depletion of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice. Additionally, we examine the therapeutic sensitivities of inactivation of Ataxia Telangiectasia Mutated (ATM), a critical DNA repair gene not infrequently mutated in pancreatic cancers. We find that ATM-depleted pancreatic cancer cell lines have no added sensitivity to several chemotherapeutic agents, but are markedly sensitive to radiotherapy. These data contribute new considerations for existing therapeutic candidates and open the door to a new set of potentially-targetable pathways for disease management.
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Keywords
PanIN, RNA-seq, pancreatic cancer, PDAC, ATM