Decoding Aneuploidy in Breast Cancer.

Khalid N. Al-Zahrani, PhD
Postdoctoral Research Fellow
Centre for Molecular and Systems Biology
Lunenfeld-Tanenbaum Research Institute
Toronto, ON, Canada

This conference is hosted by Woong-Kyung Suh, PhD. This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

About this conference
Chromosome instability is highly prevalent in cancer and drives large scale chromosomal imbalances, known as aneuploidies. However, how aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers ofgenes affected. Here, we develop a CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immune-competent mouse models of cancer. We developed a compendium of the ten most frequently altered human chromosome arms in basal-like breast cancer (BLBC), a copy number-driven disease. Using CRISPR-KOALA we screened the mouse orthologs of all 3,752 genes on these arms and identified 90 cancer driver genes, the vast majority of which havehitherto unknown functions in cancer. These genes drive distinct signalling pathways including MAPK, Hippo and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes theneed for copy number alterations (CNAs) in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene that lies adjacent to the immune checkpoint gene CD274/PD-L1 on chr9p and show that its tumor-promoting activity is associated with the creation of highly stress-resistant mitochondria that promote tumor cellsurvival. Thus, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogenous biological processes.
 

About Khalid Al-Zahrani
Dr. Khalid Al-Zahrani completed his Ph.D. in the Department of Cellular and Molecular Medicine at the University of Ottawa under the mentorship of Dr. Luc Sabourin. His doctoral work focused on mechanisms of lineage plasticity in early breast cancer initiation using mouse models of cancer. He is currently a postdoctoral research fellow at the Lunenfeld-Tanenbaum Research Institute in Toronto with Drs. Jeff Wrana and Daniel Schramek. Dr. Al-Zahrani's current focus is on developing and applying new in vivo functional genomics tools to accelerate the discovery of precision medicine targets in cancer.

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