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 MITFhigh 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 MITFlow 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.

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

“…Analysis of whole-exome sequencing data revealed only a few mutations previously identified as associated with acquired resistance to targeted drugs. It is in line with the current view that in parallel to genetic alterations, melanoma cell-autonomous mechanisms of resistance can rely on complex transcriptomic adaptations supported by epigenetic regulations, including miRNA-mediated mechanisms, and extended by the interplay between tumor and stromal cells that involves cell-cell interactions, paracrine stimulation and extracellular vesicles to create a resistance-permissive niche [39][40][41][42][43][44][45][46]. Mechanisms of resistance primarily directed to support proliferation and survival of cancer cells implicate a plethora of transcriptional regulators, adaptive responses, and feedback loops that extensively affect melanoma cell phenotype enabling the expansion of distinct cell subpopulations in the presence of drug(s) [27,[47][48][49][50][51][52].…”

Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAFV600Emelanoma cells

“…In this context, low receptor levels are a likely explanation for the short duration of pulses: once RTKs bind ligand they are efficiently endocytosed and degraded, terminating signaling. It appears that multiple growth factors and receptors can substitute for each other (EGF, NRG1, FGF8, HGF in the current work), perhaps explaining why fully characterizing the microenvironment or blocking its contributions to resistance is challenging (Ahmed and Haass, 2018). The spatial heterogeneity of spontaneous ERK pulsing likely arises from localized release of autocrine/paracrine factors enhanced by low and nonuniform distribution of RTKs at a single cell level (Spencer et al, 2009) (Shaffer et al, 2017).…”

Fibronectin in Cancer: Friend or Foe

“…Most importantly, it has been demonstrated that, likely due to XIAP-dependent pathway, drug-resistant tumor cells often highly express endogenous FN and are highly metastatic under hypoxic conditions [92,233,234]. Accumulating evidence indicates that cancer stemness and drug resistance do make tumor cells grow significantly slower [235,236]. These findings explain exactly why FN plays roles in suppressing early tumor growth and progression but promoting late cancer metastasis.…”