Mechanisms of S100A9-mediated brain metastasis

Approximately 50% of patients with EGFR-mutant lung cancer develop brain metastasis (BM), which is associated with poor prognosis and accelerated mortality. There is a long-term unmet need to better define and target the molecular mechanisms underlying BM in EGFR-mutant lung cancer. We recently identified S100A9 as a key mediator of BM. Our collaborative preliminary studies demonstrate that (i) high S100A9 expression correlates with aggressive BM and therapy resistance in mouse models and patients with EGFR-mutant lung cancer; (ii) depletion of S100A9 suppresses BM in mouse models; (iii) expression of S100A9 is epigenetically driven by both histone lysine methylation and the MEIS1 transcription factor; (iv) S100A9 exhibits a non- canonical nuclear function that transcriptionally activates pro-metastatic pathways in the brain. Therefore, the goal of our proposal is to identify potentially targetable up- and down-stream mechanisms of S100A9-mediated BM to develop more effective therapeutic strategies to treat BM in EGFR-mutant lung cancer. To this end, we will employ a multidisciplinary approach that leverages the complementary expertise of the Acharyya and Lu labs, spanning from cancer metastasis biology and modeling to chromatin biology and epigenomics. In Aim 1, we will test the hypothesis that S100A9 expression in BM-proficient S100A9-high expressing cells is regulated by the collective actions of histone H3K36 and H3K27 methylation and MEIS1-mediated transcription, using a combination of epigenome-profiling and -editing technologies. In Aim 2, we hypothesize that S100A9 induces BM by functioning as a transcriptional activator to drive expression of the pro-metastatic gene CES1, which alters lipid metabolism. We will employ immunocompetent and patient-derived BM models and slice assays to investigate how chromatin-bound S100A9 promotes BM through CES1 activation and whether pharmacological inhibition of CES1 can suppress BM in vivo. Our proposal represents the first study to explore the epigenetic regulation and nuclear function of S100A9 in BM. These studies are impactful because they will nominate actionable therapeutic approaches to target S100A9, with far-reaching clinical implications for the development of effective BM therapies for cancer patients.