Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

Abstract

In melanoma, as well as in other solid tumors, the cells within a given tumor exhibit strong morphological, functional and molecular heterogeneity that might reflect the existence of different cancer cell populations, among which are melanoma-initiating cells (MICs) with 'stemness' properties and their differentiated, fast-growing progeny. The existence of a slow-growing population might explain the resistance of melanoma to classical chemotherapies that target fast growing cells. Therefore, elucidating the biologic properties of MICs and, more importantly, the molecular mechanisms that drive the transition between MICs and their proliferating progeny needs to be addressed to develop an efficient melanoma therapy. Using B16 mouse melanoma cells and syngeneic mice, we show that the inhibition of microphthalmiaassociated transcription factor (Mitf), the master regulator of melanocyte differentiation, increases the tumorigenic potential of melanoma cells and upregulates the stem cell markers Oct4 and Nanog. Notably, p27, the CDK inhibitor, is increased in Mitf-depleted cells and is required for exacerbation of the tumorigenic properties of melanoma cells. Further, a slow-growing population with low-Mitf level and high tumorigenic potential exists spontaneously in melanoma. Ablation of this population dramatically decreases tumor formation. Importantly, these data were confirmed using human melanoma cell lines and freshly isolated human melanoma cell from lymph node and skin melanoma metastasis. Taken together our data, identified Mitf and p27 as the key molecular switches that control the transition between MICs and their differentiated progeny. Eradication of low-Mitf cells might be an appealing strategy to cure melanoma.

A novel hypoxia-associated subset of FN1highMITFlow melanoma cells: identification, characterization, and prognostic value

“…39,42 Other epithelial-to-mesenchymal transition-regulatory transcription factors like SNAI1 and SNAI2 are not expressed in the FN1 high MITF low melanoma cells; SNAI1/2 are early epithelial-to-mesenchymal transition markers implicated in the initial induction of a migratory phenotype, whereas ZEB1 is an important regulator of the maintenance of this phenotype. 40,43 MITF was recently proposed as the transcriptional switch that drives stem-like melanoma cells toward differentiation, 29 which is in line with our hypothesis that FN1 high MITF low melanoma cells may represent a reservoir of slow-cycling stemlike/tumor-driving cells. Interestingly, hypoxia represses MITF expression and thereby enhances the metastatic potential of melanoma cells.…”

“…The ultrastructural features of high nucleocytoplasmic ratio, condensed heterochromatin and immature organelles (melanosomes and mitochondria) indicate a poorly differentiated status and suggest a link with stem-like melanoma cells. [26][27][28] This association is further supported by little or no expression of the melanocytic marker MITF 29 and the unique and high expression of FN1 indicative of an epithelial-to-mesenchymal transition-linked phenotype. 7 Furthermore, gene expression analysis of microdissected FN1 high melanoma cells revealed expression of other epithelial-to-mesenchymal transition (SNAI1 and ZEB1) and previously proposed stem-like melanoma cell markers (ABCB5, HIF2A, JARID1B, and NGFR).…”

Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells

“…It should be mentioned that several reports suggest that MITF might have an anti-melanoma activity. Indeed, MITF overexpression prevented xenograft tumour development (Carreira et al, 2006;Cheli et al, 2011). It was also reported that MITF upregulated the expression of two cyclin kinase inhibitors, CDKN2A (Loercher et al, 2005) and CDKN1A (Carreira et al, 2005), and MITF depletion was demonstrated to increase melanoma cell migration in vitro (Carreira et al, 2006).…”

A picture of Mitf in melanoma immortality

“…But do the Mitf-low population truly exhibit stem-like properties? Cheli et al (2011) from Robert Ballotti's group in Nice now provide an answer. They show that short-term depletion of Mitf leads to an increase in expression of markers of stemness such as Oct4 and Nanog and that strikingly, although these cells were G1 arrested with high p27 and did not express other reported markers of melanoma stem cells such as ABCB5 or CD271, they nevertheless gave rise to larger allograft tumors.…”