Abstract 5425: MITF/TFE regulatory programs in neural crest migration are co-opted in melanoma metastasis

Abstract Introduction: Microphthalmia-associated transcription factor (MITF) is a critical regulator of melanocyte differentiation and melanoma oncogenesis. Melanoma expression profiling has revealed a strong trend between low MITF expression levels and invasive behavior. However, it is unclear how low levels of MITF are connected to invasive behavior. Preliminary data from our lab has identified transcription factor E3 (TFE3), a MITF paralog, as a transcriptional regulator in MITF-low melanoma states. We hypothesize that in melanoma cells with low MITF levels, TFE3 promotes invasion. To assess the possibility that the antagonistic regulatory interaction between MITF and a paralog was coopted from the embryo, we examine migratory behavior of neural crest cells in zebrafish embryos that are wild-type, mitfa loss-of-function (LOF) mutants, tfec (TF3 ortholog) LOF mutants, or mitfa/tfec double LOF embryos. Methods: We evaluated TFE3 levels by Western blot in a panel of melanoma cell lines known to express a range of MITF expression levels. We mutated TFE3 exon 4, which encodes the DNA binding domain, using a single guide RNA, and assessed cellular invasive potential using an in vitro transwell invasion assay. CUT Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5425.