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In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Brain-specific genetic alterations were not detected; however, MBM cells in vitro displayed lower proliferation rates and MBM-specific protein expression patterns associated with proliferation, DNA damage, adhesion, and migration. MBM lines displayed higher levels of RAC1 expression, involving a distinct RAC1-PAK1-JNK1 signaling network. RAC1 knockdown or treatment with small molecule inhibitors contributed to a less aggressive MBM phenotype in vitro, while RAC1 knockdown in vivo led to reduced tumor volumes and delayed tumor appearance. Proliferation, adhesion, and migration were higher in MBM vs nonMBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that despite their genetic variability, MBM engage specific molecular processes such as RAC1 signaling to adapt to the brain microenvironment and this can be used for the molecular characterization and treatment of brain metastases.<\/jats:p><\/jats:sec>","DOI":"10.1093\/neuonc\/noac212","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T20:23:56Z","timestamp":1662063836000},"page":"674-686","source":"Crossref","is-referenced-by-count":6,"title":["A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells"],"prefix":"10.1093","volume":"25","author":[{"given":"Ioana","family":"Stejerean-Todoran","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Physiology, Molecular Physiology, University Medical Center \u00a0 G\u00f6ttingen, G\u00f6ttingen , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phyllis A","family":"Gimotty","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Informatics and Epidemiology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Watters","sequence":"additional","affiliation":[{"name":"Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Brafford","sequence":"additional","affiliation":[{"name":"Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute , Philadelphia, Pennsylvania, 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O","family":"Rizzoli","sequence":"additional","affiliation":[{"name":"Department of Neuro- and Sensory Physiology, University Medical Center \u00a0 G\u00f6ttingen, G\u00f6ttingen , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley","family":"Garman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Translational Medicine and Human Genetics; Abramson Cancer Center; University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine L","family":"Nathanson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Translational Medicine and Human Genetics; Abramson Cancer Center; University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania, 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Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon B","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, MD Anderson Cancer Center, University of Texas , Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, MD Anderson Cancer Center, University of Texas , Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P","family":"Sch\u00f6n","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center G\u00f6ttingen , G\u00f6ttingen , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Bogeski","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Molecular Physiology, University Medical 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