1. CRISPR activation screen in mice identifies novel membrane proteins enhancing pulmonary metastatic colonisation
- Author
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Roy Rabbie, Jyoti S. Choudhary, Vivek Iyer, Victoria Harle, Anneliese O. Speak, Andrew D. Campbell, Louise van der Weyden, Mark Tullett, David J. Adams, Agnieszka Swiatkowska, Gemma Turner, Victoria Offord, Alastair Droop, Owen J. Sansom, Mercedes Pardo, Mark J. Arends, and Ingrid Ferreira
- Subjects
0301 basic medicine ,Male ,Lung Neoplasms ,Skin Neoplasms ,Melanoma, Experimental ,Medicine (miscellaneous) ,Metastasis ,Mice ,0302 clinical medicine ,Cell Movement ,Mice, Inbred NOD ,CRISPR ,Biology (General) ,Regulation of gene expression ,Mice, Knockout ,Melanoma ,interferon ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Female ,General Agricultural and Biological Sciences ,SLC4A3 ,QH301-705.5 ,colonisation ,General Biochemistry, Genetics and Molecular Biology ,lung ,dCas9 ,03 medical and health sciences ,CRISPRa ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,melanoma ,Animals ,Humans ,Neoplasm Invasiveness ,neoplasms ,mouse ,business.industry ,Cancer ,Membrane Proteins ,Biologie moléculaire ,TM4SF19 ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,LRRN4CL ,Membrane protein ,Cancer research ,Skin cancer ,CRISPR-Cas Systems ,business - Abstract
Melanoma represents ~5% of all cutaneous malignancies, yet accounts for the majority of skin cancer deaths due to its propensity to metastasise. To develop new therapies, novel target molecules must to be identified and the accessibility of cell surface proteins makes them attractive targets. Using CRISPR activation technology, we screened a library of guide RNAs targeting membrane protein-encoding genes to identify cell surface molecules whose upregulation enhances the metastatic pulmonary colonisation capabilities of tumour cells in vivo. We show that upregulated expression of the cell surface protein LRRN4CL led to increased pulmonary metastases in mice. Critically, LRRN4CL expression was elevated in melanoma patient samples, with high expression levels correlating with decreased survival. Collectively, our findings uncover an unappreciated role for LRRN4CL in the outcome of melanoma patients and identifies a potential therapeutic target and biomarker., info:eu-repo/semantics/published
- Published
- 2021
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