Ricerc@Sapienza

Metastases account for the great majority of cancer-associated deaths, in particular for Non-small cell lung cancer (NSCLC) patients, yet remain the least understood aspect of cancer biology. NSCLC comprises two histologic subtypes: lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). LAC has some preferential sites for metastases e.g. brain, bones. Interestingly, brain metastases (BM) are often seen from LAC, whereas SCC invades locally in the thoracic wall. Indeed, BM araised from LAC represent 40-60% of BM cases [1].
The influence of cellular metabolism on the selectivity of the final destination of LAC metastases is still unclear. We believe that a key contribution is given by specific microenvironments, which better meet the metabolic needs of cancer cells by providing specific metabolites and therefore can be considered "pre-metastatic niches". This would drive the development of metastases in specific sites rather than in others.
Serine/Glycine Metabolism (SGM) is a crucial factor in several cancer types. Serine hydroxymethyltransferase (SHMT), a key enzyme in SGM, catalyses the reversible interconversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-THF. SHMT exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. It contributes to antioxidant molecules and nucleotides biosynthesis. Our preliminary results demonstrate that A549 LAC cells sense the microenvironment and genetically cope with it by remodelling their metabolism and regulating the expression of the two SHMT isoforms. Under metabolic restrictions, Ser and Gly are able to restore the normal levels of SHMTs and of the serine synthesis pathway enzymes, to increase the energetic status of A459 cells and to boost their metastatic power. In this project, I will further investigate this process to obtain a complete picture of the metabolic reprogramming of cancer cells underlying brain metastasis formation by NSLC.
1-Patchell RA. 2003. Cancer Treat Rev 29:533-540