Grant: CIHR Fellowship

Cancerous tumours are populations of cells which are subject to Darwinian evolution - mutations which enhance cell survival or proliferation tend to become more common in the tumour over time through natural selection and may eventually impact clinical features. Genetic diversity within a population is the raw material which evolution sculpts and increased genetic diversity improves the chances that a tumour can evolve to overcome new challenges. A process that drastically increases tumour genetic diversity is whole-genome doubling (WGD). By doubling the number of copies of each gene, WGD increases the chances that advantageous mutations will arise and buffers the effect of harmful mutations. As WGD is common across cancer types (~30% of primary tumours), finding strategies to target WGD or predict its impact on disease course is critical but remains an open research area. I propose a detailed study into the impacts of WGD on the cell and how it shapes tumour evolution in non-small cell lung cancer. I will use novel long-read and single-cell sequencing technologies to profile WGD at a higher resolution than previously possible. I will develop algorithms to precisely identify the point when WGD occurs during the course of tumour evolution and study its impact on treatment resistance and metastasis. I will also examine the impact of WGD on gene regulation to understand how WGD alters dynamic cell states and functions. Finally, I will explore the interplay between WGD and the local tissue and immune environment. Understanding how tumours co-evolve with the immune system is critical for developing effective immunotherapy strategies. By holistically characterizing the impacts of WGD, this work can uncover new, widely applicable, therapeutic targets or biomarkers strategies to guide treatment decisions.