PRE2023- MECANISMOS REGULADORES DE PLASTICIDAD DE MELANOMA Y METASTASIS CEREBRALES (PID2022-141613OB-I00)

Effective treatments for brain metastases (BMs) constitute an urgent unmet clinical need. Clinical evidence shows that brain metastases differ from metastases in other organs as they respond differently to treatment. Several studies have suggested that tumor cells that metastasize to the brain may harbor specific intrinsic characteristics, but the unique microenvironment of the brain greatly contributes to these differences. Interestingly, the mechanisms that allow cancer cells to adapt to the brain microenvironment remains poorly understood, and this is particularly true for metabolic rewiring. The specialized brain microenvironment, with limited availability of metabolic intermediates, nutrients, and oxygen, confers constraints to cancer cells that can force metabolic reprogramming for survival. Recently, we have helped to characterize metabolic rewiring as a key regulator of resistance to therapies in melanoma (Nat. Metabolism doi: 10.1038/s42255-023-00861-4). In addition, preliminary data from our BMs preclinical models and from patients indicate that melanoma cells undergo metabolic changes in the brain metastatic niche. In this project we aim to shed light into the regulation of metabolism in BMs from melanoma to uncover potential metabolic vulnerabilities that can be targeted alone or in combination with immunotherapies to improve current therapeutic strategies.