title: RSK1 activation promotes invasion in nodular melanoma.
abstract: The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize.
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Amel
authors.initials: A
authors.lastname: Salhi
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Farhadian
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Giles
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Eleazar
authors.initials: E
authors.lastname: Vega-Saenz de Miera
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Ines P
authors.initials: IP
authors.lastname: Silva
authors.affiliation: Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Bourque
authors.affiliation: Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Karen
authors.initials: K
authors.lastname: Yeh
authors.affiliation: Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chhangawala
authors.affiliation: New York University Langone Medical Center Perlmutter Cancer Center, New York University Center for Health Informatics and Bioinformatics, New York, New York.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, New York.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, New York.
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando-Monge
authors.affiliation: Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Yariv
authors.initials: Y
authors.lastname: Houvras
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York; Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Electronic address: iman.osman@nyumc.org.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish
chemical_list: C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa