Cancer Stem Cells and the Slow Cycling Phenotype: How to Cut the Gordian Knot Driving Resistance to Therapy in Melanoma

Abstract

Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely (1) kinases and metabolic changes, (2) melanoma-associated proteins, (3) Hippo pathway and (4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

“…The therapeutic armamentarium in melanoma now comprises immune checkpoint inhibitors (ICIs) and targeted therapy in the adjuvant and metastatic settings, and these agents are also being investigated in the pre-surgical setting. Tumor cells are able to evade immune surveillance in some ways, including the activation of immune checkpoint pathways that suppress the antitumor immune response, and overexpress the ligand for PD-1 (programmed cell ligand PD-1 or PD-L1), which facilitates the escape from the immune system ( 2 ).…”

Editorial on Special Issue “Advances and Novel Treatment Options in Metastatic Melanoma”

“…Cancer stem cells (CSCs) represent one of the causes for development of resistance, thus contributing to the disease relapse following an initial response. A bioinformatic approach led to the identification of four major clusters of CSCs in BRAF mutated melanoma [8].…”

SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

“…Nuclear accumulation of YAP has been described in a variety of cancers [ 39 – 43 ], resulting in activation of target genes mainly involved in cell proliferation. Remarkably, YAP activation has been reported to be associated with stemness [ 44 ], conversion of normal fibroblasts to cancer-associated fibroblasts (CAFs) [ 45 ], and resistance to BRAF and/or MEK inhibitors [ 46 , 47 ]. Specifically, YAP confers resistance to BRAF inhibitors by inducing actin cytoskeleton remodeling in melanoma [ 48 ] and other tumors [ 49 ], and cytoskeletal tension itself has been shown to affect chemotherapeutic drug sensitivity of cancer cells [ 50 ].…”