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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)318
Number of pages17
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
Publication statusPublished - Dec 17 2018

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Stearoyl-CoA Desaturase
Neoplastic Stem Cells
Mitogen-Activated Protein Kinase Kinases
Melanoma
Drug Resistance
Polymerase Chain Reaction
Computational Biology
Treatment Failure
Lipid Metabolism
Fluorescent Antibody Technique
Disease Progression
Lung Neoplasms
Up-Regulation
Down-Regulation
Maintenance
Pharmacology

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Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma. / Pisanu, Maria Elena; Maugeri-Saccà, Marcello; Fattore, Luigi; Bruschini, Sara; De Vitis, Claudia; Tabbì, Eugenio; Bellei, Barbara; Migliano, Emilia; Kovacs, Daniela; Camera, Emanuela; Picardo, Mauro; Jakopin, Ziga; Cippitelli, Claudia; Bartolazzi, Armando; Raffa, Salvatore; Torrisi, Maria Rosaria; Fulciniti, Franco; Ascierto, Paolo A; Ciliberto, Gennaro; Mancini, Rita.

In: Journal of Experimental and Clinical Cancer Research, Vol. 37, No. 1, 17.12.2018, p. 318.

Research output: Contribution to journalArticle

Pisanu, ME, Maugeri-Saccà, M, Fattore, L, Bruschini, S, De Vitis, C, Tabbì, E, Bellei, B, Migliano, E, Kovacs, D, Camera, E, Picardo, M, Jakopin, Z, Cippitelli, C, Bartolazzi, A, Raffa, S, Torrisi, MR, Fulciniti, F, Ascierto, PA, Ciliberto, G & Mancini, R 2018, 'Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma', Journal of Experimental and Clinical Cancer Research, vol. 37, no. 1, pp. 318. https://doi.org/10.1186/s13046-018-0989-7
Pisanu, Maria Elena ; Maugeri-Saccà, Marcello ; Fattore, Luigi ; Bruschini, Sara ; De Vitis, Claudia ; Tabbì, Eugenio ; Bellei, Barbara ; Migliano, Emilia ; Kovacs, Daniela ; Camera, Emanuela ; Picardo, Mauro ; Jakopin, Ziga ; Cippitelli, Claudia ; Bartolazzi, Armando ; Raffa, Salvatore ; Torrisi, Maria Rosaria ; Fulciniti, Franco ; Ascierto, Paolo A ; Ciliberto, Gennaro ; Mancini, Rita. / Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma. In: Journal of Experimental and Clinical Cancer Research. 2018 ; Vol. 37, No. 1. pp. 318.
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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.",
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TY - JOUR

T1 - Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

AU - Pisanu, Maria Elena

AU - Maugeri-Saccà, Marcello

AU - Fattore, Luigi

AU - Bruschini, Sara

AU - De Vitis, Claudia

AU - Tabbì, Eugenio

AU - Bellei, Barbara

AU - Migliano, Emilia

AU - Kovacs, Daniela

AU - Camera, Emanuela

AU - Picardo, Mauro

AU - Jakopin, Ziga

AU - Cippitelli, Claudia

AU - Bartolazzi, Armando

AU - Raffa, Salvatore

AU - Torrisi, Maria Rosaria

AU - Fulciniti, Franco

AU - Ascierto, Paolo A

AU - Ciliberto, Gennaro

AU - Mancini, Rita

PY - 2018/12/17

Y1 - 2018/12/17

N2 - 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.

AB - 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.

U2 - 10.1186/s13046-018-0989-7

DO - 10.1186/s13046-018-0989-7

M3 - Article

C2 - 30558661

VL - 37

SP - 318

JO - Journal of Experimental and Clinical Cancer Research

JF - Journal of Experimental and Clinical Cancer Research

SN - 0392-9078

IS - 1

ER -