Abstract 1547: Melanotransferrin (MELTF, CD228) as a determinant of melanomagenesis: MELTF expression attenuates melanoma progression in the A375-luc2 murine metastasis model and human patients

Abstract

Abstract The cell-surface glycoprotein melanotransferrin (MELTF, CD228) is a member of the iron-binding transferrin superfamily expressed in human melanocytes and other cell types. Dysregulated MELTF expression in malignant melanoma has been reported before but its specific role in tumorigenesis has remained elusive. Following our interest in the role of the transferrin receptor (TFRC) in melanomagenesis, our initial TCGA-analysis suggested that high MELTF expression is associated with increased melanoma patient survival. In order to explore the mechanistic role of MELTF in melanoma we performed CRISPR/Cas9-based MELTF deletion in A375-luc2 human malignant melanoma cells. ICP/MS-analysis indicated no difference in iron-content between MELTF_WT and MELTF_KO cells. NanoString nCounterTM ('PanCancer-Progression-Panel'; 770 genes) comparative transcriptomic profiling (MELTF_KO versus MELTF_WT) demonstrated an upregulation of EMT-related expression networks in MELTF_KO cells, an observation consistent with phenotypic detection of enhanced matrigel invasiveness; likewise, inclusion of recombinant glycosylated MELTF (Gly20-Gly711 His-tag; 92 kDa; 10-100 nM) attenuated invasiveness of MELTF_KO cells. In SCID mice, subcutaneous growth of MELTF_KO exceeded that of MELTF_WT xenografts, and intracardial injection followed by non-invasive bioluminescent monitoring revealed an increase in lung metastatic burden associated with decreased survival of the MELTF_KO group. These data support a heretofore unrecognized tumor-suppressive function of MELTF expression in melanoma progression, a mechanistic role consistent with a potential survival benefit associated with high MELTF expression observed in human melanoma patients. Citation Format: Jana Jandova, Georg T. Wondrak. Melanotransferrin (MELTF, CD228) as a determinant of melanomagenesis: MELTF expression attenuates melanoma progression in the A375-luc2 murine metastasis model and human patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1547.