Parvez Vora1,2, Mathieu Seyfrid1,2, Chitra Venugopal1,2, Maleeha A Qazi1,3, Sabra Salim3, Ruth Isserlin4, Minomi Subapanditha1, Erin O'Farrell1,3, Sujeivan Mahendram1,2, Mohini Singh3, David Bakhshinyan1,3, Chirayu Chokshi1,3, Nicole McFarlane1,2, Anna Dvorkin-Gheva5, Kevin R Brown4, Naresh Murty2, Jason Moffat4, Gary D Bader4, Sheila K Singh6,7,8. 1. Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. 2. Department of Surgery, McMaster University, Hamilton, ON, Canada. 3. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. 4. Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 5. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. 6. Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca. 7. Department of Surgery, McMaster University, Hamilton, ON, Canada. ssingh@mcmaster.ca. 8. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. ssingh@mcmaster.ca.
Abstract
PURPOSE: Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.
PURPOSE:Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.