Lung cancer metastasis is a challenging clinical problem with enormous implications for patients and possible therapeutic options able to address this unmet need are required. While other aspects of metastasis formation have been investigated in more detail, the importance of metabolic adaptation is largely unexplored, but recent evidences indicate that it may play a significant role in the progression of lung cancer and colonization at distant sites. Brain is a preferential target organ of lung cancer cells and metastases frequently arise from lung primary tumors in this district of the organism. In this project we will mainly focus on the mechanism of metabolic adaptation that allow lung cancer cells to activate functions that precede proliferation at the final site of metastasis, in order to shed light on the factors which allow selection of the brain as the target organ in which metastasis will develop. Based on our preliminary results, we envisage that selected amino acids, forming the Brain Amino Acids pool (BAA pool) might be important factors driving lung cancer cells into the brain. To tackle this problem, we plan to pursue two aims: in the first one, we plan to elucidate in vitro the molecular mechanisms and pathways linking BAA uptake to remodeling of central and energy metabolism that enable lung cancer cells to migrate in synthetic and brain-derived media, while in the second part of the project we will further investigate this hypothesis ex-vivo, using patient-derived databases and tissue samples, and in vivo, using a mouse model, to assess the therapeutic potential of selected compounds to decrease brain metastases from lung cancer cells.