Novel Function of Metastasin-1 in Non-Small Cell Lung Cancer

The majority of patients with advanced stage non-small cell lung cancer (NSCLC) die within 18 months of diagnosis, in which metastasis accounts for 90% of cancer death. Cancer metastasis is a multiple-step process in which the metabolic changes of cancer cells are dynamic and linked to every step of the metastatic process. Metastasin-1 (Mts-1), also called S100A4, is an established metastasis promoting protein. NDUFS2 (NADH dehydrogenase ((ubiquinone)) Fe-S protein 2) is a subunit of complex I in the mitochondrial respiratory chain. Our preliminary data demonstrated that Mts-1 drove the invasive capacity and enhanced cellular respiration and cells with depleted Mts-1 shifted their metabolism toward glycolysis, while decreased glycolytic capacity in response to glycolysis inhibitor. Interestingly, we found that Mts-1 positively regulated NDUFS2. The objective of this proposal is to dissect the role of Mts-1 in cellular respiration of lung cancer cells and the therapeutic potential of targeting cancer metabolism through modulation of Mts-1. Based on our preliminary data, we hypothesize that Mts-1 drives the plasticity of mitochondrial metabolic networks which in turn dysregulates lung cancer cells apoptosis, promotes NSCLC cell proliferation, invasion and metastasis, and thus, represents a novel and viable target to treat advanced NSCLC. To test this hypothesis, we will elucidate the mechanisms by which Mts-1 mediated mitochondrial metabolism promotes the invasive capacity of NSCLC cells. We will use lung cancer cells with Mts-1 and/or NDUFS2 modulations to test that Mts-1 upregulates NDUFS2 expression, activates mitochondrial complex I activity, therefore, facilities cellular respiration to promote NSCLC proliferation, invasion and invasive growth. We will also propose to determine the therapeutic implication of targeting mitochondrial metabolism through Mts-1 modulation in lung cancer. For this, we will utilize lung cancer cell lines and the in vivo metastasis mouse model to test that depletion of Mts-1 sensitizes lung cancer cell response to glycolysis inhibitors. Should our hypothesis proven correct, it will introduce the foundation of further investigating the link between cancer cell metabolism and metastatic process. It will also allow us to explore a novel and more effective strategy to treat advanced NSCLC.