Project 466734

Cancer has permeated through our population and touched Canadians in all walks of life. Nearly 1 in 2 Canadians are expected to be diagnosed with cancer in their lifetime and cancer is the leading cause of death in Canada. Metastasis (the spread of cancer) accounts for over 90% of cancer related deaths. Despite advances in cancer treatments, metastatic disease remains largely incurable. Metastatic lesions are established by circulating tumour cells (CTCs) which are shed from the primary tumour into the bloodstream. As the source of metastasis, CTCs are attractive markers for diagnosis and prognosis and as therapeutic targets. Thus, the characterization of the molecular and genetic mechanisms of CTCs may aid the development of novel treatments for metastasis.CRISPR/Cas9 is a gene editing technology that can be leveraged for functional genomic screens. Functional genomic screens systematically modify gene function to observe the effect of the modification. CRISPR screens systematically knock out or delete genes and were recently used to discover a key regulator of metastasis in CTCs. Although CRISPR screens can identify key targets of metastasis, the condition often requires a complete loss of expression. Recapitulating the effect pharmacologically is difficult since drugs typically only modulate expression. To discover the drivers of metastasis in CTCs that are actionable drug targets, we propose to modify the CRISPR screen to a CRISPR activation (CRISPRa) screen of CTCs. A CRISPRa screen will systematically increase expression of genes on a genome wide scale, thus will discover genes whose increased expression modulates CTCs characteristics and drives metastasis. This will enable the discovery of more actionable drug targets to treat metastasis.