Elucidating the Role of BMI1 in Lung and Colon Tumor Maintenance and Progression

Abstract

Cancer is a highly dynamic disease characterized by dedifferentiation, heterogeneity, and plasticity. It is postulated that within heterogeneous tumor tissues, there exists a subpopulation of cells, termed cancer stem cells (CSCs), with the ability to initiate and support tumor growth, promote metastatic spreading, and drive relapse following chemoradiotherapy. Given the high tumorigenic potential of these cells, there is strong interest in identifying methods to specifically target and eradicate CSCs. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) is an epigenetic regulator important for stem cell self-renewal and differentiation, and it is also a proto-oncogene that is overexpressed in a wide variety of cancer types. Given its role in normal stem cell biology and its overexpression in cancer, there is strong interest in inhibiting BMI1 as a method of targeting CSCs. In this thesis, I will examine the role of BMI1 in tumor initiation, maintenance, and progression in lung and colon cancer, two cancer types in which BMI1 is overexpressed. Using genetically engineered mouse models, we determine that in oncogenic KRAS-driven lung adenocarcinomas, with or without Trp53 deletion, genetic ablation of Bmi1 at tumor initiation induces a pronounced proliferation defect and consequently significant suppression of tumor development and thus extension of lifespan. In stark contrast, Bmi1 deletion in established lung adenocarcinomas does not impair tumor progression, CSC numbers or capacity, or metastatic potential, and instead, upregulates transcriptional programs associated with lung adenocarcinoma dedifferentiation and progression. Similarly, Bmi1 deletion in established colon tumors does not impair colon cancer progression. Our work demonstrates that the effects of BMI1 loss are highly dependent on the context and timing of deletion relative to tumor development, and our findings raise concern over the use of BMI1 inhibitors as cancer treatments.