Abstract PO-025: BMI1 is required for human and murine pancreatic cancer progression and controls metabolism and cell proliferation

Abstract

Pancreatic cancer is the third leading cause of cancer-related death in the United States, and deeper understanding into factors that control its progression will be key to developing future treatments. Previously, we showed that Bmi1 is required for the initiation of pancreatic cancer in mice, and enhances growth of pancreatic cancer cells in vitro. However, the role of Bmi1 in established tumors and the mechanisms underlying its requirement have so far been elusive. To investigate this, we used a CRISPR/Cas9 strategy to delete BMI1 in primary cell lines derived from human pancreatic tumors as well as murine pancreatic cancer cell lines, and created clonal lines lacking BMI1 expression. We then used subcutaneous tumor growth models as well as transcriptomic and metabolomic profiling to define the role of BMI1 expression in tumor growth. BMI1 knockdown in human and mouse pancreatic cancer cells resulted in slower growth in vitro and in vivo compared to controls. Histologically, control tumors were moderately differentiated, while BMI1-/- tumors were small or histologically undetectable. BMI1-/- tumors with sufficient tumor tissue displayed prominent extracellular mucin pools, with few cancer cell clusters interspersed within mucin and dead cell debris. Interestingly, the remaining cancer cells in the BMI1-/- tumors, identified by CK19 immunostaining, still expressed phosphorylated ERK, indicating MAPK pathway activation, as expected in Kras mutant cells. Thus, BMI1 expression was required for the growth of both human and murine pancreatic cancer cells. Given this, we sought to determine the functional processes regulated by BMI1 to facilitate pancreatic cancer growth by using both transcriptomic and metabolomic comparison of WT or BMI1-/- human pancreatic cancer cells. Further analysis revealed changes in pathways with known importance in pancreatic cancer, including many related to metabolism and cell proliferation. Strikingly, the expression of every enzyme in the glycolytic pathway was downregulated in BMI1-/- cells. Loss of BMI1 also resulted in changes in pathways that control cell proliferation, and specifically the G2/M checkpoint, possibly explaining the growth defect observed in vitro and in vivo. Together, our data show that BMI1 is a key regulator of essential cellular processes for human and mouse pancreatic cancer growth, including metabolism and cell cycle progression. Further study will be required to determine the exact mechanism of BMI1 regulation of these pathways, as well as its potential as a therapeutic target in pancreatic cancer.

Citation Format: Heather K. Schofield, Christopher J. Halbrook, Annachiara Del Vecchio, Donovan Drouillard, Zeribe C Nwosu, Joyce K. Thompson, Carlos Espinoza, Yaqing Zhang, Costas A Lyssiotis, Marina Pasca di Magliano, Filip Bednar. BMI1 is required for human and murine pancreatic cancer progression and controls metabolism and cell proliferation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-025.