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Guest Post by Professor Margaret Ashcroft: CRISPR/Cas9 screening

Urological Malignancies programme member, Professor Margaret Ashcroft and her team of researchers recently published their work on CRISPR/Cas9 screening in Nature's Communications Biology. In this guest post, Professor Ashcroft summarises the paper.

Professor Margaret Ashcroft

A recent study by the Ashcroft group, with input from colleagues at the Wellcome Sanger Institute, describes an unbiased genome-wide CRISPR/Cas9 screening approach to identify genes essential for tumour cell viability under different metabolic conditions, including hypoxia (low oxygen).

Hypoxia activates the hypoxia inducible factor (HIF) transcriptional programme which can profoundly impact mitochondrial function, and lead to metabolic adaptive responses, enabling tumour cells to survive and evade treatment. Notably, certain urological malignancies such as clear cell renal cell carcinoma (ccRCC) exhibit constitutive HIF activation which drives tumour development. Moreover, mitochondrial oxidative phosphorylation (OXPHOS) is a prominent change associated with metastatic ccRCC. Therefore, discovering new ways to target metabolic adaptive responses in cancer is of intense interest.

The results of the study published in Communications Biology provide a comprehensive survey of nuclear-encoded mitochondrial genome, and classifies genes that are commonly essential across different tumour cell types (625 tumour cell lines). The study shows that twice as many nuclear-encoded mitochondrial genes are common essential genes when compared to the genome as a whole. Furthermore, the group discovered that certain genes, when targeted, provide a switch in tumour cell viability depending on the metabolic conditions, and they identify certain genes that specifically promote tumour viability in hypoxia.

The study provides a resource of potential therapeutic targets that could have applicability across different cancer types.

Thomas, L.W., Esposito, C., Morgan, R.E. et al. Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia. Commun Biol 4, 615 (2021). https://doi.org/10.1038/s42003-021-02098-x

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