Abstract
Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.
Highlights
It has long been recognized that tumor cells can display remarkable variability in almost every phenotypic trait
Two key molecules identified in melanoma phenotype switching are the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor POU3F24, 8
Intra-vital imaging of an engineered mouse melanoma cell line, expressing GFP driven by a BRN2 promoter, has demonstrated motile, invasive cells leaving the site of the primary tumor had high expression of BRN2 while lacking pigmentation suggesting loss of MITF expression[17]
Summary
It has long been recognized that tumor cells can display remarkable variability in almost every phenotypic trait. Intra-vital imaging of an engineered mouse melanoma cell line, expressing GFP driven by a BRN2 promoter, has demonstrated motile, invasive cells leaving the site of the primary tumor had high expression of BRN2 while lacking pigmentation suggesting loss of MITF expression[17] These authors showed that switching was possible in both directions, switching from a BRN2-high state to a BRN2-low state was favored over -low to -high switching in metastases. Our results show that while MITF controls proliferation, migration and invasion in vitro, expression of both MITF and BRN2 was important for metastatic growth in vivo These results are in contrast to previous findings, and highlight the importance of expression of both BRN2 and MITF transcription factors in development of melanoma metastasis
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