ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors.
Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75highstem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Geoffrey
G
Richard
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Dermatology Unit, Hospices Civils de Lyon CH Lyon Sud, Pierre Bénite Cedex, France.
Stéphane
S
Dalle
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Marie-Ambre
MA
Monet
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Maud
M
Ligier
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Dermatology Unit, Hospices Civils de Lyon CH Lyon Sud, Pierre Bénite Cedex, France.
Amélie
A
Boespflug
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Roxane M
RM
Pommier
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Department of Biopathology, Centre Léon Bérard, Lyon, France.
Arnaud
A
de la Fouchardière
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Dermatology Unit, Hospices Civils de Lyon CH Lyon Sud, Pierre Bénite Cedex, France.
Marie
M
Perier-Muzet
Department of Biopathology, Hospices Civils de Lyon CH Lyon Sud, Pierre-Bénite Cedex, France.
Lauriane
L
Depaepe
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Romain
R
Barnault
Department of Biopathology, Hospices Civils de Lyon CH Lyon Sud, Pierre-Bénite Cedex, France.
Garance
G
Tondeur
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
Stéphane
S
Ansieau
Fondation Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
Emilie
E
Thomas
INSERM U1065 Equipe 1 Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome Equipe labellisée Ligue 2013 Centre Méditerranéen de Médecine Moléculaire, Nice, France Université de Nice Sophia-Antipolis UFR Médecine, Nice, France CHU Nice Service de Dermatologie, Nice, France.
Corine
C
Bertolotto
INSERM U1065 Equipe 1 Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome Equipe labellisée Ligue 2013 Centre Méditerranéen de Médecine Moléculaire, Nice, France Université de Nice Sophia-Antipolis UFR Médecine, Nice, France CHU Nice Service de Dermatologie, Nice, France.
Robert
R
Ballotti
APHP INSERM U976 Saint Louis Hospital Pharmacology-Genetic Laboratory Paris, Paris, France.
Samia
S
Mourah
Department of Pathology, INSERM U1165 Université Paris Diderot AP-HP Hôpital Saint-Louis, Paris, France.
Maxime
M
Battistella
Department of Dermatology, APHP Saint Louis Hospital, Paris, France INSERM U976 University Paris 7 Diderot, Paris, France.
Céleste
C
Lebbé
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Dermatology Unit, Hospices Civils de Lyon CH Lyon Sud, Pierre Bénite Cedex, France.
Luc
L
Thomas
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France Institut Universitaire de France, Paris, France alain.puisieux@lyon.unicancer.fr julie.caramel@lyon.unicancer.fr.
Alain
A
Puisieux
Cancer Research Center of Lyon, INSERM U1052, Lyon, France Cancer Research Center of Lyon, CNRS UMR 5286, Lyon, France Université de Lyon, Lyon, France ISPB Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France alain.puisieux@lyon.unicancer.fr julie.caramel@lyon.unicancer.fr.
Julie
0000-0002-8883-918X
J
Caramel
D000222:Adaptation, Physiological; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000066670:Cell Plasticity; D004351:Drug Resistance; D006801:Humans; D008544:Melanocytes / Q000187:drug effects* / Q000502:physiology*; D008545:Melanoma / Q000188:drug therapy / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1

EMT
; 
MAPK
; melanoma; resistance; targeted therapy