Membrane protein regulators of melanoma pulmonary colonisation identified using a CRISPRa screen and spontaneous metastasis assay in mice.

G3 : Genes - Genomes - Genetics
Louise van der WeydenDavid J Adams

Abstract

Metastasis is the spread of cancer cells to a secondary site within the body, and is the leading cause of death for cancer patients. The lung is a common site of metastasis for many cancer types, including melanoma. Identifying the genes involved in aiding metastasis of melanoma cells to the lungs is critical for the development of better treatments. As the accessibility of cell surface proteins make them attractive therapeutic targets, we performed a CRISPR activation screen using a library of guide RNAs (gRNAs) targeting the transcription start sites of 2,195 membrane protein-encoding genes, to identify genes whose upregulated expression aided pulmonary metastasis. Immunodeficient mice were subcutaneously injected in the flank with murine B16-F0 melanoma cells expressing dCas9 and the membrane protein library gRNAs, and their lungs collected after 14-21 days. Analysis was performed to identify the gRNAs that were enriched in the lungs relative to those present in the cells at the time of administration (day 0). We identified six genes whose increased expression promotes lung metastasis. These genes included several with well-characterised pro-metastatic roles (Fut7, Mgat5 and Pcdh7) that have not previously been linked to mel...Continue Reading

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