SMARCB1 Maintains Lineage Fidelity in Clear Cell Renal Cell Carcinoma
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Authors
Wesolowski, Ludovic
Advisors
Vanharanta, Sakari
Date
2022-06-15Awarding Institution
University of Cambridge
Qualification
Doctor of Philosophy (PhD)
Type
Thesis
Metadata
Show full item recordCitation
Wesolowski, L. (2022). SMARCB1 Maintains Lineage Fidelity in Clear Cell Renal Cell Carcinoma (Doctoral thesis). https://doi.org/10.17863/CAM.80269
Abstract
Lineage-specific transcription factors have emerged as a promising class of essential genes in cancer.
The best examples of leveraging this phenomenon in the clinic is targeting the androgen receptor and
the oestrogen receptor in prostate and breast cancer respectively. Despite the success of these
therapies, the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether
lineage factor pathways could be exploited in other cancer types remain poorly understood. Using clear
cell renal cell carcinoma (ccRCC) as a model, I characterise mechanisms that underlie lineage factor
dependence in cancer. Using CRISPR/Cas9 loss-of-function screening coupled with in vitro and in vivo
validation I show that the loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex,
confers an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. SMARCB1
knockout (KO) leads to large-scale loss of a kidney-specific enhancer program, conversion to a cellular
state resembling that of rhabdoid tumours, and the re-activation of proliferative pathways. Using a
second CRISPR/Cas9 screen, I show that these proliferative pathways are underpinned by the
acquisition of new transcriptional dependencies. These dependencies represent rare essential genes
across different lineage-specific and oncogenic pathways, a principle validated in a large-scale
CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. In summary, dependence on
tissue-specific lineage factors in cancer can be modulated via epigenetic remodelling.
Keywords
Cancer, SMARCB1, PAX8, Lineage, ccRCC, Renal cancer, CRISPR screen
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.80269
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