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.

Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity

“…PPAR α and γ are positioned at crossing points between lipid metabolism and transcription, balancing and reciprocally cross-linking developmental homeostatic processes, that are established between classic cancer hallmarks, e.g., between tumor cell differentiation and immune surveillance, or immune response and the inflammatory status ( 26 , 77 – 79 ). The expression profiles of PPARs in tumor tissues under changing phenotypic conditions are not well studied, yet ( 56 ).…”

“…By adding temsirolimus to the pioglitazone arm of the melanoma editing schedule, long-term melanoma control was achieved in patients with extensive liver metastases of uveal melanoma by efficacious M-CRAC control ( 79 , 80 , 155 ).…”

BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers

“…An interesting finding reported in several studies is that FA metabolism correlates with MITF levels [ 175 ]. In addition, several studies have extensively demonstrated the driving role of the NAMPT/NAD axis or serine–glycine metabolism and glutamine metabolism (glutaminase, GLS) in the acquisition of resistance to BRAFi [ 176 ].…”

Alterations in Plasma Lipid Profiles Associated with Melanoma and Therapy Resistance

“…Metastatic disease progression and drug resistance are associated with metabolic reprogramming and dysregulated lipid metabolism [3,4]. Alterations of lipid regulatory pathways, including pathways controlling cholesterol (CHOL), fatty acid (FA) synthesis [5][6][7], and sphingolipids (SL) metabolism [8,9], have been associated with disease progression and resistance to kinase inhibitors (KI), both in patients' tumors and in cell lines model systems.…”