A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells

2022 | journal article. A publication of Göttingen

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​A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells​
Stejerean-Todoran, I.; Gimotty, P. A.; Watters, A.; Brafford, P.; Krepler, C.; Godok, T. & Li, H. et al.​ (2022) 
Neuro-Oncology, art. noac212​.​ DOI: https://doi.org/10.1093/neuonc/noac212 

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Stejerean-Todoran, Ioana; Gimotty, Phyllis A.; Watters, Andrea; Brafford, Patricia; Krepler, Clemens; Godok, Tetiana; Li, Haiyin; Bonilla del Rio, Zuriñe; Zieseniß, Anke ; Katschinski, Dörthe M. ; Vultur, Adina
Abstract Background Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. 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. Methods 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. Results 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. non-MBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels. Conclusions 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.
Issue Date
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | P17: Die Rolle mitochondrialer Kontaktstellen im Rahmen tumorrelevanter Calcium- und Redox-Signalwege 
Institut für Herz- und Kreislaufphysiologie ; Universitätsmedizin Göttingen ; Institut für Neuro- und Sinnesphysiologie ; Klinik für Dermatologie, Venerologie und Allergologie 
Working Group
RG Bogeski 
RG Rizzoli (Quantitative Synaptology in Space and Time) 



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