PACM-08 UNCOVERING A ROLE FOR ST6GALNAC3-DRIVEN ABERRANT SIALYLATION IN MELANOMA BRAIN METASTASIS

Abstract

Brain metastasis (BM) is a clinically devastating sequelae of cutaneous melanoma. Cutaneous melanoma has an exceptionally high propensity to metastasize to the brain and results in increased morbidity and mortality. Melanoma brain metastasis (MBM) is clinically evident in 40-70% of metastatic melanoma patients. While immune checkpoint inhibition has revolutionized the landscape of treatment for metastatic melanoma, effective therapies for patients with MBM are greatly needed and there is a critically unmet need for improved treatment options tailored to the unique biology of MBM. Analysis of bulk transcriptomic and proteomic datasets contrasting MBM and non-MBM (NBM) samples revealed that expression of the sialyltransferase ST6GALNAC3 is consistently increased in MBM compared to NBM samples. The upregulation of ST6GALNAC3 in MBM suggests a role for aberrant sialylation in the development of brain metastasis, and we hypothesize that melanoma cells overexpressing ST6GALNAC3 engage in aberrant sialylation of O-glycoproteins that facilitates the development of MBM. shRNA-mediated silencing of ST6GALNAC3 in human melanoma short term cultures leads to decreased establishment of MBM upon intracardiac injection into immunodeficient mice, and ectopic overexpression of ST6GALNAC3 increases overall metastatic burden. To identify the enzymatic substrates of ST6GALNAC3 that might mediate the effects of its dysregulation in MBM we undertook a proximity labeling approach and identified several candidate genes of interest. Exploration of the sialylation-dependent function of these candidate genes in the setting of MBM will reveal the mechanism through which they promote the development of BM and may uncover novel therapeutic avenues for the treatment and prevention of MBM.