MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment

Abstract

Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-α instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF-stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-α into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITFlow/c-Junhigh syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenvironment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITFlow/c-Junhigh melanomas to counteract their growth-promoting and immunosuppressive functions.

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

“…Smith et al (2014) reported that TNFα promotes melanoma growth and therapeutic resistance by up-regulating MITF, which should promote differentiation. In contrast, other studies report that TNFα down-regulates MITF (Landsberg et al 2012;Konieczkowski et al 2014;Riesenberg et al 2015), decreases differentiation, and promotes a slow-cycling phenotype (Ostyn et al 2014), a characteristic of MITF-low cells (Cheli et al 2011b). Significantly, a recently described melanoma TNFα response gene set (Riesenberg et al 2015) positively correlated with the GSS score in the TCGA melanoma cohort as well as the single-cell RNA-seq patient-derived melanoma data from Tirosh et al (2016) (Fig.…”

“…The moving average expression of individual genes of interest or averaged signatures were calculated using a sample window size of n = 20, and trend lines were added to the bar plots. An R-skript for calculating and generating moving average plots of TCGA cancer cohorts implementing TCGA access via cBioportal was provided in our previous study (Riesenberg et al 2015). Significance of the Spearman rank correlation was determined by an asymptotic Spearman correlation test using the original log 2 expression values and not the moving average values.…”

“…However, while short-term depletion of MITF leads to invasiveness and adoption of a tumor-initiating phenotype (Cheli et al 2011b), longer-term MITF depletion leads to senescence (Giuliano et al 2010). However, in vivo senescence is largely restricted to nevi (Michaloglou et al 2005;Gray-Schopfer et al 2006), although melanomas can contain many MITF-negative cells (Goodall et al 2008;Riesenberg et al 2015). How MITF is downregulated in vivo without provoking senescence is unknown, but low MITF is correlated with resistance to MEK and BRAF inhibitors (Konieczkowski et al 2014;Muller et al 2014;Dugo et al 2015).…”

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

“…49 MITF also repressed ZEB1 transcription in the 501mel human melanoma cell line, 50 as well as inflammation genes through repressing c-Jun expression in mouse and human melanoma cell lines. 51 MITF recruits RBPJK as a cofactor in repressing transcription of microRNAs miR-221 and miR-222 in human melanoma cell lines. 52 It remains mechanistically unclear how MITF represses target genes and what functional roles MITF has through repressing gene expression.…”

Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells

“…46,47 Furthermore, repression of MITF expression could make melanoma to recruit myeloid immune cells into the tumor microenvironment which could counteract tumor growth promoting and immunosuppressive functions. 48 Besides, MITF was related to intrinsic drug resistance and the drug resistance to BRAF inhibitors in melanoma cells, which could further promote cell survival and proliferation. 49,50 Melanoma cells expressing MITF highly displayed significant drug resistance in BRAF-i and MEK-i treatment.…”