Genome-wide in vivo screen of circulating tumor cells identifies SLIT2 as a regulator of metastasis

Author:

Xia Fan1ORCID,Ma Yuan12ORCID,Chen Kangfu1ORCID,Duong Bill3ORCID,Ahmed Sharif1ORCID,Atwal Randy14,Philpott David5ORCID,Ketela Troy6,Pantea Jennifer1,Lin Sichun7ORCID,Angers Stephane178ORCID,Kelley Shana O.134910ORCID

Affiliation:

1. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada.

2. Key Laboratory of Tribology, Tsinghua University, Beijing 100084, P.R. China.

3. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.

4. Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.

5. Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.

6. Princess Margret Genomics Centre, University Health Network, Toronto, Ontario, Canada.

7. Donnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

8. Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, ON, Canada.

9. Department of Chemistry, Northwestern University, Evanston, IL, USA.

10. Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.

Abstract

Circulating tumor cells (CTCs) break free from primary tumors and travel through the circulation system to seed metastatic tumors, which are the major cause of death from cancer. The identification of the major genetic factors that enhance production and persistence of CTCs in the bloodstream at a whole genome level would enable more comprehensive molecular mechanisms of metastasis to be elucidated and the identification of novel therapeutic targets, but this remains a challenging task due to the heterogeneity and extreme rarity of CTCs. Here, we describe an in vivo genome-wide CRISPR knockout screen using CTCs directly isolated from a mouse xenograft. This screen elucidated SLIT2 —a gene encoding a secreted protein acting as a cellular migration cue—as the most significantly represented gene knockout in the CTC population. SLIT2 knockout cells are highly metastatic with hypermigratory and mesenchymal phenotype, resulting in enhanced cancer progression in xenograft models.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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