Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Abstract

Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.

Keywords: MITF; drug resisitance; fatty acids; heterogeneity; melanoma; metabolic plasticity; mitochondria.

FIGURE 1

Metabolic roles of MITF in melanoma. The transcription factor MITF, known to regulate melanoma plasticity and cell identity, may play such a role also through the direct regulation of specific genes crucially involved in several metabolic functions. By modulating metabolic events such as the TCA cycle, mitochondrial biogenesis, nutrient sensing, the hypoxia response, angiogenesis, autophagy, lysosome biogenesis and fatty acid desaturation, MITF tunes cell proliferation, and prevents the stabilization of an invasive phenotype.

FIGURE 2

Metabolic features and routes towards invasion and metastasis. Melanomas, subjected to microenvironment-driven non-genetic heterogeneity, are composed of several cell subsets, which express different levels of MITF and display specific metabolic features that provide a distinct identity. Eventually, as a consequence of such a reversible identity and as a first step of the metastatic process, some cells acquire invasive capacity and escape from the primary tumor. Migrating cells can adapt to the extrinsic insults affecting them. FA metabolism may provide melanoma cells with survival advantages that facilitate the metastatic process. The main dynamic microenvironmental cues that lead to melanoma phenotypic changes are nutrients, drugs, and inflammatory signals (not represented in the figure). Melanoma cells respond to changes in these parameters adapting their metabolism, at least in part, through the activation of the ISR. The ISR works in melanoma as a microenvironment-sensing pathway that modulates cell phenotype and metabolic activity, alone or in coordination with other key nutrient sensing pathways, like mTORC1.