Researchers have identified four genes that act as metastasis suppressors in triple-negative breast cancer, according to a study published in Nature Communications. The team conducted an unbiased genome-wide CRISPR/Cas9 loss-of-function screen in a breast cancer xenograft model to isolate tumor-intrinsic mechanisms that control metastatic progression.
The functional genomics screen uncovered four clinically relevant metastasis suppressor genes: VPS45, CMTR2, RBSN, and NF2. Disruption of these genes accelerated lung colonization in the xenograft models. Experimental validation revealed that depletion of these genes promoted several stages of cancer spread, including epithelial-to-mesenchymal transition, cell migration, invasion, intravasation, and angiogenesis. In contrast, using CRISPR-mediated activation to boost the expression of these genes suppressed metastatic spread.
Patient data integrated into the study confirmed that lower expression levels of VPS45, CMTR2, RBSN, and NF2 correlate with advanced disease in human tumors. Patients showing higher expression levels exhibited trends toward improved outcomes. The study also observed distinct vascular effects linked to CMTR2, where loss of the gene triggered vascular remodeling and intratumoral heterogeneity, indicating a specific role in tumor-vascular interactions.
The research was conducted by scientists at the McGill University Health Centre in Montreal and Assiut University in Egypt. The study was led by Jean-Jacques Lebrun, with Leslie Chaltel Lima and Ni Wang contributing equally as co-first authors, alongside Soaad Galal, Cléo Moury, Gang Yan, Meiou Dai, and Suhad Ali.
The Canadian Institutes for Health Research provided operating grant funding for the study. Additional funding and scholarship support came from the Fonds de recherche du Québec – Santé, the Egyptian Ministry of Higher Education, and the Canadian Cancer Research Society. Breast cancer SUM cell lines used in the project were provided by Dr. Stephen Ethier, and imaging dye was supplied by MediLumine Inc.
