A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma.
Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients.
Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; LabEX DEVweCAN, 69008 Lyon, France; University Lyon I, 69008 Lyon, France; Université de Lyon, 69000 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
Julie
J
Caramel
Eftychios
E
Papadogeorgakis
Louise
L
Hill
Gareth J
GJ
Browne
Geoffrey
G
Richard
Anne
A
Wierinckx
Gerald
G
Saldanha
Joy
J
Osborne
Peter
P
Hutchinson
Gina
G
Tse
Joël
J
Lachuer
Alain
A
Puisieux
J Howard
JH
Pringle
Stéphane
S
Ansieau
Eugene
E
Tulchinsky
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D018450:Disease Progression; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D048049:Extracellular Signal-Regulated MAP Kinases