On this ground, an efficient targeting of CSCs has been advocated as essential for obtaining long-lasting tumour remission.

Cancer stem cells (CSCs) have been involved in these long-term treatment failures.

We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ.

On this ground, we investigated the role of SCD1 in melanoma CSCs.

Methods SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patients tissues by qRT-PCR and IHC analyses.

The effects of combination of BRAFMEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively.

SCD1, YAPTAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence.

Results We first observed that SCD1 expression increases during melanoma progression.

BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors.

We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAPTAZ and downstream genes but surprisingly not SCD1.

However, SCD1 pharmacological inhibition was able to downregulate YAPTAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors.

Conclusions Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.

The advent of molecular targeted agents and immune checkpoint inhibitors consistently changed the treatment of patients with advanced melanoma, leading to an unprecedented improvement of survival outcomes 1, 2.

Randomized phase III trials demonstrated that the BRAF inhibitors namely vemurafenib and dabrafenib achieve an efficient targeting of BRAF-mutated melanoma 3.

Given that functional evidence pointed to continued activation of the MAPK pathway as a way cancer cells exploit to overcome the roadblock imposed by BRAF inhibitors, combining BRAF and MEK inhibitors resulted in improved clinical outcomes compared to single agent BRAF-directed therapy 4, 5, 6.

Despite these therapeutic successes, melanoma cells acquire the ability to withstand combined BRAF and MEK inhibition.

A number of molecular mechanisms, eventually co-existing, have been proposed in the attempt of explaining how melanoma cells adapt to prolonged inhibition of BRAF and MEK.

Currently, evidence converge on the functional or mutational reactivation of the MAPK pathway or, alternatively, activation of parallel signalling avenues 7, 8, 9, 10, 11.

Adding further complexity to this picture is the existence, within the same tumour, of distinct cell clones relying on different survival pathways.

A concept that acquired increased attention over the past two decades is the existence of an uncommon subpopulation of tumour cells with distinctive features, defined as cancer stem cells (CSCs).

This definition is rooted into their ability to self-renew and capability to propagate the tumour upon xenotransplantation in immunocompromised mice 12, 13, 14.

The development of dedicated assays for functional characterization of CSCs allowed to clarify two central tenets of CSCs biology.

First, the CSC state is not a fixed condition, but rather a condition that can be acquired when cells are exposed to specific stimuli deriving from the microenvironment (e.g.

H, epithelial-mesenchymal transition, cytokines) 15, 16, 17, 18, 19.

Indeed, while cytotoxic agents eliminate more differentiated, quickly dividing cells, the CSC pool expands in the attempt of replacing dying tumour cells.

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