Biological actions and therapeutic targeting of S100A4/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. S100A4, also called metastasin-1, is an established metastasis promoting protein. The objective of this proposal is to unravel the contribution of S100A4 to the invasive phenotype of NSCLC cells and to target S100A4 genetically or through FDA-approved drugs, such as Niclosamide, to mitigate the progression of NSCLC. We hypothesize that S100A4 deregulates apoptosis, promotes proliferation, invasion and metastasis, and represents a novel and viable target for the treatment of advanced NSCLC. To test this hypothesis, we will first elucidate the mechanisms by which S100A4 drives the invasive behavior of NSCLC cells. We will use established lung cancer cell lines to determine that S100A4 sustains NF-êB activation through S100A4 autocrine action and S100A4 mediated p53 inactivation to promote lung cancer cell proliferation, invasion and metastasis. Second, we will define the clinical implications of S100A4 expression in patient-derived NSCLC specimens. We will utilize lung cancer tissue microarrays (TMAs) and matched plasma from NSCLC patients to evaluate S100A4 expression and test S100A4 expression is associated with lung cancer progression, and S100A4 serum levels represent a marker of poor prognosis. Finally, we will determine the effectiveness of targeting S100A4 to block the invasive behavior of NSCLC in vivo by genetically manipulating S100A4 expression or repurposing Niclosamide to test S100A4 is a viable target in NSCLC and can be effectively modulated by FDA-approved drugs.