New research from scientists at the Wellcome Sanger Institute has revealed a gene that plays a key role in metastasis of cancers to the lungs.
Metastasis is the spread of cancer cells to a secondary site. It is the leading cause of death in cancer patients – accounting for 90% of cancer deaths. The process of metastatic dissemination of a tumour involves multiple steps, including tumour cell invasion of lymphatics and/or blood vessels, survival in circulation and also extravasation at a distant site. To become a clinically relevant metastasis, the disseminated tumour cells (DTCs) must proliferate and colonise the secondary site. The regulation of DTC growth at the secondary site can determine metastatic outcomes.
The lungs are common sites of metastasis across many different cancer types. This is in part due to the fact that both blood and lymphatic fluids are pumped through the pulmonary microvasculature. More than 80% of metastatic melanoma patients initially show the involvement of only one distant organ site (mainly the lungs). Controlling metastatic colonisation in the lungs is a critical component of patient management.
CRISPR activation screen
Cell surface proteins are important in the metastatic process, playing key roles in both signalling and adhesion interactions. They represent attractive drug and immunological targets due to their accessibility. Traditionally, researchers have used mass-spectrometry-based proteomics to identify these proteins. In this study, published in Communications Biology, researchers applied CRISPR activation technology to screen a library of guide RNAs targeting membrane protein encoding genes. They used an experimental metastasis assay with melanoma cells in mice. They specifically set out to identify genes whose overexpression resulted in the increased ability of melanoma cells to spread to the lungs in mice.
The team found that upregulated expression of the cell surface protein LRRN4CL led to increased pulmonary metastases in mice. They also checked databases of gene expression in patient tumours, revealing elevated expression of LRRN4CL. Higher levels of expression also correlated with decreased survival.
LRRN4CL represents an attractive drug target. It easier to target with drugs as it is on the surface and is also expressed at low levels elsewhere in the body, reducing serious side effects.
Dr David Adams, senior author of the paper from the Wellcome Sanger Institute, stated:
“Prior to this study, there was nothing in the scientific literature to link the LRRN4CL gene to cancer, much less to suggest that it plays such a pivotal role in metastasis. Part of the power of CRISPR screens is that they don’t require a clear hypothesis to create new insights. This is an important discovery that marks LRRN4CL as a promising drug target to help prevent the spread of cancer to the lungs and improve outcomes for patients.”
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