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Updated: Jul 19, 2025
CD Spectroscopy to Study DNA-Protein Interactions
Published on: February 10, 2022
The SWI/SNF complex member SMARCB1 supports lineage fidelity in kidney cancer
Ludovic Wesolowski1, Jianfeng Ge1,2, Leticia Castillon3
1MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge CB2 0XZ, UK.
Abstract:
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.
Insights
Loss of SMARCB1 in clear cell renal cell carcinoma (ccRCC) cells enables lineage switching, promoting resistance to therapy. This study reveals how cancer cells lose lineage fidelity and adapt to new dependencies.
Area of Science:
- Oncology
- Cancer Biology
- Epigenetics
Background:
- Lineage switching is a mechanism of cancer therapy resistance.
- The maintenance and loss of lineage fidelity in cancer are not well understood.
Purpose of the Study:
- To investigate the mechanisms underlying lineage switching in clear cell renal cell carcinoma (ccRCC).
- To identify genetic factors that influence lineage fidelity and therapy resistance.
Main Methods:
- CRISPR-Cas9 genetic screening was employed to identify genes involved in lineage switching.
- Analysis of epigenetic programs and gene dependencies in ccRCC cells.
Main Results:
- Loss of SMARCB1 (SWI/SNF chromatin remodeling complex) confers resistance to renal lineage factor (PAX8) inhibition in ccRCC.
- SMARCB1 inactivation leads to loss of kidney-specific epigenetic programs and adoption of new gene dependencies.
- Lineage-switched ccRCC cells exhibit morphological features of neuroendocrine differentiation but lack molecular markers.
Conclusions:
- SMARCB1 is crucial for maintaining lineage fidelity in ccRCC.
- Understanding lineage switching dynamics can inform the development of more effective cancer therapies.
- Targeting lineage factor dependencies may overcome therapy resistance.
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