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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

Authors: Maria Elena Pisanu, Marcello Maugeri-Saccà, Luigi Fattore, Sara Bruschini, Claudia De Vitis, Eugenio Tabbì, Barbara Bellei, Emilia Migliano, Daniela Kovacs, Emanuela Camera, Mauro Picardo, Ziga Jakopin, Claudia Cippitelli, Armando Bartolazzi, Salvatore Raffa, Maria Rosaria Torrisi, Franco Fulciniti, Paolo A. Ascierto, Gennaro Ciliberto, Rita Mancini

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. 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 patient’s tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi 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, YAP/TAZ 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 YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ 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.
Appendix
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Metadata
Title
Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma
Authors
Maria Elena Pisanu
Marcello Maugeri-Saccà
Luigi Fattore
Sara Bruschini
Claudia De Vitis
Eugenio Tabbì
Barbara Bellei
Emilia Migliano
Daniela Kovacs
Emanuela Camera
Mauro Picardo
Ziga Jakopin
Claudia Cippitelli
Armando Bartolazzi
Salvatore Raffa
Maria Rosaria Torrisi
Franco Fulciniti
Paolo A. Ascierto
Gennaro Ciliberto
Rita Mancini
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0989-7

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