The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance

Abstract

Advanced cutaneous melanoma is the deadliest form of skin cancer and one of the most aggressive human cancers. Targeted therapies (TT) against BRAF mutated melanoma and immune checkpoints blockade therapies (ICB) have been a breakthrough in the treatment of metastatic melanoma. However, therapy-driven resistance remains a major hurdle in the clinical management of the metastatic disease. Besides shaping the tumor microenvironment, current treatments impact transition states to promote melanoma cell phenotypic plasticity and intratumor heterogeneity, which compromise treatment efficacy and clinical outcomes. In this context, mesenchymal-like dedifferentiated melanoma cells exhibit a remarkable ability to autonomously assemble their own extracellular matrix (ECM) and to biomechanically adapt in response to therapeutic insults, thereby fueling tumor relapse. Here, we review recent studies that highlight mechanical phenotypic plasticity of melanoma cells as a hallmark of adaptive and non-genetic resistance to treatment and emerging driver in cross-resistance to TT and ICB. We also discuss how targeting BRAF-mutant dedifferentiated cells and ECM-based mechanotransduction pathways may overcome melanoma cross-resistance.

The Efficacy of Zinc Phthalocyanine Nanoconjugate on Melanoma Cells Grown as Three-Dimensional Multicellular Tumour Spheroids

“…Moreover, these treatments have limitations such as a poor bioavailability and off-target toxicity, killing neighbouring healthy cells [ 1 ]. Melanoma resistance to therapies is also attributed to the intrinsic heterogeneity of tumours, which promotes their survival and aggressiveness [ 4 ]. In addition, there is a scarcity of specific genetic mutations that are targetable by currently available treatment modalities, limiting the alternatives for melanoma treatment [ 5 ].…”

Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma

“…Phenotype plasticity, closely intertwined with non-mutational transcriptional and epigenetic reprogramming, is an emerging hallmark of cancer (42) and is referred to as phenotype switching in melanoma (2, 43). Next to epigenetic changes, cues from the tumour microenvironment (TME) like biochemical and biophysical properties are thought to play crucial roles in phenotype transition (44). PXDN has the potential to affect several properties of the TME, either via its catalytic activities (45, 46) or via protein-protein interactions, through its typical protein binding domains, which include a leucine-rich repeat domain, four C-like immunoglobulin domains and a von Willebrand factor type C module (47).…”

Single-cell RNA sequencing in melanoma: what have we learned so far?

“…Melanoma cells are intrinsically plastic and can rapidly adapt and respond to various extracellular stresses, including to drug treatments, inflammation, nutrient and oxygen deprivation. 31 This adaptation involves a cellular switch to multiple but discrete phenotypes within a single tumour and may be analogous to the epithelial to mesenchymal transition seen in other cancer cell types. However, melanoma cells are not epithelial-like, and instead, the phenotype transition is reversible and occurs across a continuous trajectory, transitioning between a differentiated and a dedifferentiated cellular state.…”