ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors

被引:97
作者
Richard, Geoffrey [1 ,2 ,3 ,4 ,5 ]
Dalle, Stephane [1 ,2 ,3 ,4 ,5 ,6 ]
Monet, Marie-Ambre [1 ,2 ,3 ,4 ,5 ]
Ligier, Maud [1 ,2 ,3 ,4 ,5 ]
Boespflug, Amelie [1 ,2 ,3 ,4 ,5 ,6 ]
Pommier, Roxane M. [1 ,2 ,3 ,4 ,5 ]
de la Fouchardiere, Arnaud [1 ,2 ,3 ,4 ,5 ,7 ]
Perier-Muzet, Marie [1 ,2 ,3 ,4 ,5 ,6 ]
Depaepe, Lauriane [8 ]
Barnault, Romain [1 ,2 ,3 ,4 ,5 ]
Tondeur, Garance [8 ]
Ansieau, Stephane [1 ,2 ,3 ,4 ,5 ]
Thomas, Emilie [9 ]
Bertolotto, Corine [10 ,11 ,12 ]
Ballotti, Robert [10 ,11 ,12 ]
Mourah, Samia [13 ]
Battistella, Maxime [14 ]
Lebbe, Celeste [15 ,16 ]
Thomas, Luc [1 ,2 ,3 ,4 ,5 ,6 ]
Puisieux, Alain [1 ,2 ,3 ,4 ,5 ,17 ]
Caramel, Julie [1 ,2 ,3 ,4 ,5 ]
机构
[1] INSERM, Canc Res Ctr Lyon, U1052, Lyon, France
[2] CNRS, Canc Res Ctr Lyon, UMR 5286, Lyon, France
[3] Univ Lyon, Lyon, France
[4] Univ Lyon 1, ISPB, Lyon, France
[5] Ctr Leon Berard, Lyon, France
[6] CH Lyon Sud, Hosp Civils Lyon, Dermatol Unit, Pierre Benite, France
[7] Ctr Leon Berard, Dept Biopathol, Lyon, France
[8] CH Lyor Sud, Hosp Civils Lyon, Dept Biopathol, Pierre Benite, France
[9] Fdn Synergie Lyon Canc, Ctr Leon Berard, Lyon, France
[10] Ctr Mediterraneen Med Mol, Biol & Pathol Melanocytes Pigmentat Cutanee Melan, Equipe Labellisee Ligue 2013, INSERM,U1065,Equipe 1, Nice, France
[11] Univ Nice Sophia Antipolis, UFR Med, Nice, France
[12] CHU Nice, Serv Dermatol, Nice, France
[13] St Louis Hosp, APHP, Pharmacol Genet Lab Paris, INSERM,U976, Paris, France
[14] Univ Paris Diderot, Hop St Louis, AP HP, Dept Pathol,INSERM,U1165, Paris, France
[15] St Louis Hosp, APHP, Dept Dermatol, Paris, France
[16] Univ Paris 7 Diderot, INSERM, U976, Paris, France
[17] Inst Univ France, Paris, France
关键词
EMT; MAPK; melanoma; resistance; targeted therapy; EPITHELIAL-MESENCHYMAL TRANSITION; CANCER STEM-CELLS; DRUG-RESISTANCE; BRAF; EXPRESSION; ZEB1; EMT; SURVIVAL; THERAPY; IDENTIFICATION;
D O I
10.15252/emmm.201505971
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 BRAF(V600)-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/p75(high) stem-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.
引用
收藏
页码:1143 / 1161
页数:19
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