title: Brain metastasis is predetermined in early stages of cutaneous melanoma by CD44v6 expression through epigenetic regulation of the spliceosome.
abstract: Melanoma brain metastasis (MBM) is frequent and has a very poor prognosis with no current predictive factors or therapeutic molecular targets. Our study unravels the molecular alterations of cell-surface glycoprotein CD44 variants during melanoma progression to MBM. High expression of CD44 splicing variant 6 (CD44v6) in primary melanoma (PRM) and regional lymph node metastases from AJCC Stage IIIC patients significantly predicts MBM development. The expression of CD44v6 also enhances the migration of MBM cells by hyaluronic acid and hepatocyte growth factor exposure. Additionally, CD44v6-positive MBM migration is reduced by blocking with a CD44v6-specific monoclonal antibody or knocking down CD44v6 by siRNA. ESRP1 and ESRP2 splicing factors correlate with CD44v6 expression in PRM, and ESRP1 knockdown significantly decreases CD44v6 expression. However, an epigenetic silencing of ESRP1 is observed in metastatic melanoma, specifically in MBM. In advanced melanomas, CD44v6 expression correlates with PTBP1 and U2AF2 splicing factors, and PTBP1 knockdown significantly decreases CD44v6 expression. Overall, these findings open a new avenue for understanding the high affinity of melanoma to progress to MBM, suggesting CD44v6 as a potential MBM-specific factor with theranostic utility for stratifying patients.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Marzese
authors.forename: Michelle
authors.initials: M
authors.lastname: Liu
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Huynh
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirose
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Donovan
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Huynh
authors.forename: Eiji
authors.initials: E
authors.lastname: Kiyohara
authors.forename: Kelly
authors.initials: K
authors.lastname: Chong
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.forename: Ryo
authors.initials: R
authors.lastname: Tanaka
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Donald L
authors.initials: DL
authors.lastname: Morton
authors.forename: Garni
authors.initials: G
authors.lastname: Barkhoudarian
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Kelly
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012372:ROC Curve; D012261:Ribonucleoproteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017381:Spliceosomes / Q000235:genetics*; D000072668:Splicing Factor U2AF; D000096142:Cutaneous Malignant Melanoma
chemical_list: C112697:CD44v6 antigen; C539364:ESRP1 protein, human; C539365:ESRP2 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; C450006:PTBP1 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human; D038941:Polypyrimidine Tract-Binding Protein; D017228:Hepatocyte Growth Factor; D006820:Hyaluronic Acid
keywords: CD44v6; alternative splicing; brain metastasis; melanoma; spliceosome