Abstract B59: Bmi1 is required for murine pancreatic cancer initiation.

Abstract

Bmi1 is an integral component of polycomb repressor complex 1, which functions as a key epigenetic regulator during normal development. Previous work has implicated Bmi1 as a critical mediator of stem cell function with additional oncogenic functions in multiple malignancies. In this work we utilized genetic approaches to address the role of Bmi1 in murine pancreatic cancer initiation and to assess the ability of Bmi1-expressing pancreatic acinar cells to serve as the cells of origin for murine pancreatic neoplasia. We used the Pdx1-Cre, KrasLSL-G12D/+ (KC) mouse model of pancreatic ductal adenocarcinoma (PDA) and combined it with a novel conditional Bmi1 knockout mouse to generate resultant KC;Bmi1LoxP/LoxP (KBC) mice. We induced acute pancreatitis in a cohort of 4-6 week-old KC and KBC littermates by intraperitoneal (IP) injections of caerulein to drive the formation of pancreatic intraepithelial neoplasias (PanINs), the precursor lesion to pancreatic cancer. Three weeks after the induction of acute pancreatitis, the pancreata were harvested and pathological analysis was performed to determine the extent and grade of PanIN lesions as well as the presence of acinar-ductal metaplasia (ADM), which is thought to precede PanIN formation. Histological analysis of the pancreatic tissues in KC mice revealed that normal acini formed 52% (10-86%, n=4) of the pancreas while ADM and PanIN1A/B composed 45% (14-82%, n=4), while the remaining 3% was PanIN2-3. Mice lacking one allele of Bmi1 had 60% (24-86%, n=6) acini, 33% (16-56%, n=6) ADM and PanIN1A/B, with the remaining 6% of the pancreas replaced by PanIN2-3. Pancreata of KBC mice that lacked both alleles of Bmi1 were composed of 92% (88-98%, n=3) acini, 7% (2-10%, n=3) ADM, and <1% PanIN1A. This data provides the first direct evidence for the role of Bmi1 in murine pancreatic neoplasia. A rare subpopulation of Bmi1-expressing pancreatic acinar cells has been previously proposed to serve as the source of cells for pancreatic repair during pancreatitis recovery. Genetically engineered mouse models of PDA utilizing acinar cell-specific tamoxifen-inducible Cre recombinase expression (Ela-CreERT2) have also demonstrated the capacity of the acinar cells to serve as the origin of murine PanINs and PDA. To address the role of Bmi1-expressing acinar cells in pancreatic neoplasia, we combined the inducible Bmi1-IRES-CreERT2 mice with KrasLSL-G12D/+ mice to generate compound KB mice. We activated the Cre recombinase in KB mice by oral gavage with tamoxifen and subsequently induced acute pancreatitis one week later by IP injections of caerulein. Histological analysis of the harvested pancreata revealed rare areas of ADM and low-grade PanINs within 2-3 weeks after pancreatitis induction. Overall our data directly implicate Bmi1 as a key regulator in the initiation of murine pancreatic neoplasia. It also provides the first genetic evidence that Bmi1-expressing cells in the pancreas can serve as the cells of origin for pancreatic neoplasia. Citation Format: Filip Bednar, Yaqing Zhang, Daisuke Nakada, Diane M. Simeone, Sean J. Morrison, Marina Pasca di Magliano. Bmi1 is required for murine pancreatic cancer initiation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B59.