Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Abstract

An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…The plasticity of melanoma as enabler of drug resistance was a subject of most recent reviews [16,37,53]. Arozarena and Wellbrock [53] proposed three phases of response to MAPK inhibitor therapy in MITF high melanomas, initial with induced reprogramming, adaptive with enhanced drug tolerance and acquired with drug resistance.…”

“…In addition to expression of AXL, NGFR and a lineage-specific transcription factor MITF, expression of SOX transcription factors that are associated with control of cancer cell plasticity, is broadly used to classify the phenotypes of melanoma cells [36,37]. First, the expression of SOX2, SOX9, and SOX10 at the transcript levels was compared between drug-naïve cell lines.…”

The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

“…This gene regulates the expression of pigmentation related molecules, which are recognized by T-cells, thus contributing to the highly immunogenic nature of melanoma [5]. Several studies have shown that the MITF low cells are dedifferentiated, invasive, and apoptosis-resistant [6][7][8], which gives them the ability to survive harsh conditions, such as under targeted and/or immunotherapy agents [5]. Given the fact that melanomas, under harsh conditions, can become enriched in MITF low cells and that these are more capable of escaping T-cell recognition, loss of MITF may be a mechanism for tumor cells to evade the immune system [9].…”

MITF reprograms the extracellular matrix and focal adhesion in melanoma

“…Various different studies, including gene expression studies of tumours, immunohistochemical analysis of melanoma samples and singlecell sequencing studies of patient-derived xenografts suggest the existence of different cell types in melanoma tumours. This cellular heterogeneity is believed to reflect the associated ability of tumour cells to switch their phenotype from proliferative, non-invasive cells to quiescent, invasive cells and back, thus allowing metastasis and the escape from therapeutic intervention (reviewed in [8]. This has been summarized in the phenotype switching model which suggests that melanoma cells can switch between invasive and proliferative states allowing them to either grow and form tumours or metastasize to a new site [8,9].…”

“…This cellular heterogeneity is believed to reflect the associated ability of tumour cells to switch their phenotype from proliferative, non-invasive cells to quiescent, invasive cells and back, thus allowing metastasis and the escape from therapeutic intervention (reviewed in [8]. This has been summarized in the phenotype switching model which suggests that melanoma cells can switch between invasive and proliferative states allowing them to either grow and form tumours or metastasize to a new site [8,9]. Understanding the molecular mechanisms underlying the phenotypic plasticity of melanoma cells is key to addressing the metastatic potential of melanoma cells.…”