Midkine is a tumor cell survival factor that displays metastatic and therapeutic resistance functions in uveal melanoma

Abstract

Purpose : Uveal melanoma is the most common intraocular tumor in adults and displays an inherent propensity for hepatic metastases. Since metastatic tumors exhibit widespread therapeutic resistance and extremely poor survival, there is a need for new therapeutic targets and prognostic biomarkers of disease progression. Midkine was previously identified as a prognostic biomarker for several non-ocular tumors by other laboratories. We identified midkine as one of the most differentially expressed genes between primary and metastatic uveal melanoma cells. The purpose of this study is to investigate the effect of midkine expression on uveal melanoma tumor cell survival functions and disease progression.

Methods : The Cancer Genome Atlas (TCGA) database of 80 uveal melanoma patients was used to assess the associations between midkine expression levels in primary uveal melanoma samples and: (i) survival, (ii) development of metastasis, and (iii) other known staging and prognostic markers. Gain- and loss- of midkine function assays were performed to investigate the effect of midkine on tumor cell survival, proliferation and migration. Signaling arrays were used to elucidate the molecular pathways affected by midkine expression.

Results : We found a significant correlation between midkine expression in primary uveal melanoma and overall survival. Patients with high midkine expression displayed only a 20% 5-year survival, whereas patients with low midkine levels displayed a 90% survival rate. High midkine expression in the primary tumor also coincided with monosomy 3, development of metastasis, and histopathological staging parameters associated with poor prognosis. Loss-of midkine function experiments showed reduced cell proliferation, viability and an increased apoptotic rate in uveal melanoma cells. Both in a static and dynamic migration assay, we confirmed that overexpression of midkine increased tumor cell migration across a barrier of hepatic sinusoid endothelial cells.Furthermore, we demonstrated that midkine activates the Akt/mTOR pathway and promotes survival in tumor cells treated with Akt and mTOR inhibitors by maintaining phosphorylation of the mTOR target RPS6.

Conclusions : Midkine is identified as a tumor cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as therapeutic target in uveal melanoma.

This is a 2020 ARVO Annual Meeting abstract.