The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer
Ludovic Wesolowski,
Jianfeng Ge,
Leticia Castillon,
Debora Sesia,
Anna Dyas,
Shoko Hirosue,
Veronica Caraffini,
Anne Y. Warren,
Paulo Rodrigues,
Giovanni Ciriello,
Saroor A. Patel,
Sakari Vanharanta
Affiliations
Ludovic Wesolowski
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK
Jianfeng Ge
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
Leticia Castillon
Translational Cancer Medicine Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
Debora Sesia
Department of Computational Biology, University of Lausanne (UNIL), 1015 Lausanne, Switzerland; Swiss Cancer Center Leman, Lausanne, Switzerland
Anna Dyas
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK; Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
Shoko Hirosue
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK
Veronica Caraffini
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK
Anne Y. Warren
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Paulo Rodrigues
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK
Giovanni Ciriello
Department of Computational Biology, University of Lausanne (UNIL), 1015 Lausanne, Switzerland; Swiss Cancer Center Leman, Lausanne, Switzerland
Saroor A. Patel
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK
Sakari Vanharanta
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK; Translational Cancer Medicine Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; Corresponding author
Summary: Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies.
