Microenvironment-Driven Dynamic Heterogeneity and Phenotypic Plasticity as a Mechanism of Melanoma Therapy Resistance

Abstract

Drug resistance constitutes a major challenge in designing melanoma therapies. Microenvironment-driven tumor heterogeneity and plasticity play a key role in this phenomenon. Melanoma is highly heterogeneous with diverse genomic alterations and expression of different biological markers. In addition, melanoma cells are highly plastic and capable of adapting quickly to changing microenvironmental conditions. These contribute to variations in therapy response and durability between individual melanoma patients. In response to changing microenvironmental conditions, like hypoxia and nutrient starvation, proliferative melanoma cells can switch to an invasive slow-cycling state. Cells in this state are more aggressive and metastatic, and show increased intrinsic drug resistance. During continuous treatment, slow-cycling cells are enriched within the tumor and give rise to a new proliferative subpopulation with increased drug resistance, by exerting their stem cell-like behavior and phenotypic plasticity. In melanoma, the proliferative and invasive states are defined by high and low microphthalmia-associated transcription factor (MITF) expression, respectively. It has been observed that in MITF^high melanomas, inhibition of MITF increases the efficacy of targeted therapies and delays the acquisition of drug resistance. Contrarily, MITF is downregulated in melanomas with acquired drug resistance. According to the phenotype switching theory, the gene expression profile of the MITF^low state is predominantly regulated by WNT5A, AXL, and NF-κB signaling. Thus, different combinations of therapies should be effective in treating different phases of melanoma, such as the combination of targeted therapies with inhibitors of MITF expression during the initial treatment phase, but with inhibitors of WNT5A/AXL/NF-κB signaling during relapse.

Keywords: cancer drug resistance; clonality; melanoma; microphthalmia-associated transcription factor; slow-cycling tumor cells; tumor heterogeneity; tumor microenvironment; tumor plasticity.

Figure 1

Schematic representation of microenvironment-driven dynamic heterogeneity and phenotypic plasticity as a mechanism of melanoma therapy resistance. Tumor cells close to the blood vessels proliferate, while those away from blood vessels experience hypoxia and nutrient starvation that contribute to their slow-cycling phenotype. While treatment readily targets proliferating cells, slow-cycling cells can evade drug action and survive. Upon continuous treatment, this slow-cycling subpopulation is enriched within the tumor by clonal expansion. Due to their inherent cancer stem cell-like property, they are capable of self-renewal or differentiation into a proliferative tumor cells with increased drug resistance. In addition to this, the slow-cycling cells can switch their phenotype to fast proliferating cells upon exposure to oxygen and nutrients after replacing the original peripheral fast proliferating cells that had been killed by the therapy. These phenotype-switched cells might be more drug resistant too, as they might have acquired resistance during their slow-cycling phase.

Figure 2

Proposed role of microphthalmia-associated transcription factor (MITF) and WNT5A/AXL/NF-κB signaling in melanoma therapy. MITF^high melanomas could be treated initially with a combination of an MAPK pathway inhibitors (MAPKi) and an inhibitor of MITF expression. This should increase the efficacy of the MAPKi and delay the acquisition of drug resistance (104). Once in the resistance state with low MITF levels, the therapy could comprise a combination of a MAPKi and an inhibitor of WNT5A/AXL/NF-κB signaling.