Cooperative behaviour and phenotype plasticity evolve during melanoma progression

Abstract

A major challenge for managing melanoma is its tumour heterogeneity based on individual co‐existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest‐like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater “fitness,” supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter‐phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.

Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma

“…Cooperation has previously been reported both in epithelial cancers (Celià-Terrassa et al, 2012;Neelakantan et al, 2017;Tsuji et al, 2009) and between melanoma PRO and INV states in the context of primary tumor collective cell invasion (Chapman et al, 2014) and metastatic tropism (Rowling et al, 2020), but the mechanisms that explain the relationship between the PRO/INV states and cooperative metastasis have remained unknown. We provide for the first time a clear mechanism that explains how these two subpopulations, which coexist in the primary tumor, cooperate in metastasis formation.…”

Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma

“…Second, heterogeneity along the EMT axis seen in circulating tumor cells (CTCs) (Bocci et al, 2021;Yu et al, 2013) is recapitulated in melanoma CTCs too (Aya-Bonilla et al, 2020). Third, cooperation among phenotypes with varying EMT status has been witnessed during metastasis and tumor formation (Jolly and Celia-Terrassa, 2019), reminiscent of recent observations in melanoma (Rowling et al, 2020). Further investigations into the dynamics of phenotypic transitions can elucidate whether melanoma cells exhibit hysteresis (Karacosta et al, 2019) and/or spontaneous/stochastic state switching (Tripathi et al, 2020) that characterize EMT.…”

Rethinking the biology of metastatic melanoma: a holistic approach

“…However, the blood compartment is a notoriously stressful environment for CTCs, considering that < 0.1 % of CTCs in melanoma animal models metastasize [21]. As invasive melanoma cells enter the blood, phenotype switching leads to a gain in mesenchymal traits [16]. Their new liquid microenvironment lacks the supportive stroma of the primary tumor including metabolic fueling by the reverse Warburg effect.…”

“…Here, the right context-dependent metabolic "sweet spot" is achieved by utilizing the amount of glucose that is present to meet the minimal viable needs yet maximal anabolic potential. In addition to cooperation with CAFs, metabolic symbiosis is amplified by nutrient trade-off and interphenotypic communication between melanoma subsets [16][17][18][19][20]. The established intercellular "social" interaction results in tumors of greater fitness [16,17].…”