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CRISPR activation screen in mice identifies novel membrane proteins enhancing pulmonary metastatic colonisation
Louise van der Weyden1, Victoria Harle1, Gemma Turner1
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
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.
Insights
Researchers identified LRRN4CL as a cell surface protein that enhances melanoma metastasis. Elevated LRRN4CL in patients correlates with decreased survival, suggesting it as a potential therapeutic target and biomarker for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma is a deadly skin cancer due to metastasis.
- Cell surface proteins are promising therapeutic targets.
- Novel molecular targets are needed for melanoma therapy.
Purpose of the Study:
- Identify cell surface molecules that promote melanoma metastasis.
- Investigate the role of LRRN4CL in melanoma progression.
- Determine LRRN4CL's potential as a therapeutic target and biomarker.
Main Methods:
- CRISPR activation screening of membrane protein-encoding genes.
- In vivo assessment of pulmonary colonization in mouse models.
- Analysis of LRRN4CL expression in melanoma patient samples.
Main Results:
- Upregulation of LRRN4CL significantly increased pulmonary metastases in mice.
- LRRN4CL expression was elevated in human melanoma samples.
- High LRRN4CL levels correlated with reduced patient survival.
Conclusions:
- LRRN4CL plays a significant role in melanoma metastasis and patient outcomes.
- LRRN4CL is a potential therapeutic target for melanoma treatment.
- LRRN4CL serves as a prognostic biomarker for melanoma patients.
