Dottorato in SCIENZE DELLA VITA

Titolo della tesi: Role of one-carbon metabolism and cytosolic serine hydroxymethyltransferase in the brain metastatic potential of lung adenocarcinoma.

Metastatic cancer represents the major leading cause responsible for cancer mortality. The tumor microenvironment and the metabolites released by the cells of the target organs play a critical role in metastasis initiation and progression. Lung cancer is a highly aggressive tumor with poor prognosis, which often spreads to the brain. In the present work, we aimed to study the connection between the metabolism of selected amino acids produced and released in the brain and the establishment of metastases from lung cancer. Analysis of the metabolic features of lung metastases reveals that specific amino acids are able to control lung cancer metastatic potential and shed light on the role of serine and glycine. We demonstrate that these non-essential amino acids are required to ensure the motility of lung cancer cells, thus supporting the idea that formation of brain metastasis might depend on serine/glycine one-carbon metabolism (OCM). We show that motility depends on the activity of the cytosolic enzyme serine hydroxymethyltransferase (SHMT1), a key enzyme involved in the OCM, which converts glycine to serine in the cytosol. A specific level of cytosolic serine is required to maintain ATP resources, mainly by acting on glycolysis, and control redox homeostasis. This metabolic status is in turn sensed by AMP kinase (AMPK), which ultimately allows actin filaments polymerization, cytoskeleton remodeling and finally lung cancer cells migration. These results suggest that new therapeutic strategies can be designed using specific inhibitors of serine/glycine import and/or inhibitors of SHMT activity to control metastasis formation.