Absence of Enhancer of Zeste Homolog 2 Promotes the Progression of KRAS-Driven Pancreatic Ductal Adenocarcinoma

Xiaoyi Wang, The University of Western Ontario

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is estimated to be the second deadliest cancer by 2030. Previous studies showed constitutive activation of KRAS (KRAS^G12D) is a key genetic driver of PDAC, accelerated by deletion of the epigenetic regulator Enhancer of Zeste Homologue 2 (EZH2). However, contradictory findings suggest multiple roles for EZH2. The goal of this study was to define EZH2’s contributes to early KRAS^G12D-driven PDAC. I hypothesized that EZH2 restricts KRAS^G12D initiation of PDAC in response to injury. To address this hypothesis, genetically modified mice with targeted deletion of the SET domain of Ezh2 +/- KRAS^G12D were exposed to cerulein-induced pancreatic injury and examined for pancreatic lesions. Histological analysis for markers of tissue damage and inflammation showed loss of EZH2 caused no difference in the pre-neoplastic lesion formation but did affect progression, and reduced immune cell infiltration, suggesting a role for EZH2 in limiting early progression of KRAS^G12D-mediated PDAC.