Pathogenic role and therapeutic targeting of BAP1 loss in tumor metastasis

• Applicant: Dr. Samuel Peña-Llopis
• Subject Area: Nephrology ; General Genetics and Functional Genome Biology ; Biochemistry ; Bioinformatics and Theoretical Biology ; Hematology, Oncology ; Reproductive Medicine, Urology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 364397498

Kidney cancer is among the ten most prevalent cancers arising in Western countries. One third of renal cell carcinoma patients present with metastatic disease at diagnosis, and another 30% will develop metastases after surgery. When metastatic, it remains largely incurable. Tumors with BAP1 mutations are more aggressive and tend to metastasize. We have discovered that the three most upregulated microRNAs (miRNAs) in BAP1-mutated tumors constitute a miRNA cluster whose overexpression was previously reported to be involved in the promotion of metastasis in many tumor types. These results suggest that BAP1 regulates the expression of a miRNA cluster involved in metastasis. In the proposed project, we aim to investigate the molecular mechanism of repression of the expression of the miRNA cluster by BAP1 and to identify associated therapeutic opportunities. Specifically, we will (1) identify and characterize the BAP1 protein complex that binds at the miRNA cluster promoter; (2) explore the therapeutic potential of anti-miR inhibitors in the prevention and treatment of cancer metastases; and (3) uncover genetic vulnerabilities resulting from BAP1 loss by a synthetic lethality strategy.

• DFG Programme: Research Grants