The role of MITF in regulating transcriptional cell states in melanoma ; MITF og umritun í sortuæxlum

The pigment producing melanocytes are derived from the neural crest cells and form precursor cells called melanoblasts. These cells proliferate and migrate to their destination in skin, hair and other organs where they differentiate into melanocytes which produce the pigment melanin. The Microphthalmia-associated transcription factor (MITF) is indispensable for the establishment of fully differentiated melanocytes. MITF controls the expression of genes required for melanocyte survival, proliferation and differentiation. Melanoma cells thus exploit the transcriptional activity of MITF to foster cancer progression. However, the role of MITF in regulating the metastatic potential of melanoma cells is complex and often leads to inconsistent findings. The scope of this thesis was to further elucidate the functional role of MITF in melanoma development. Our findings revealed that MITF knock out (KO) melanoma cells exhibit a reduced proliferation rate compared to the control cell line. Consistent with that, the expression of cell cycle regulators that are known targets of MITF was affected in the KO cells. Surprisingly, both the migration and invasion potential of MITF-KO cells were significantly reduced compared to empty vector cell lines. In contrast, transient depletion of MITF did not affect the invasion potential of melanoma cells. RNA-sequencing followed by differential gene expression analysis revealed a gain of extracellular matrix and neuronal related genes in MITF-KO cells, whereas pigmentation genes that are specific to melanocyte differentiation were lost. Accordingly, the gene expression profile of MITF-KO cells was negatively correlated with the gene signature of melanocytes, whereas a positive correlation was observed with neural crest and Schwann cell signature. Interestingly, the major components of focal adhesions, including paxillin (PAX) and focal adhesion kinase (FAK) are direct targets of MITF and their expression was induced upon MITF depletion. Well in line, the number of FAK and PAX positive ...