TY - JOUR
T1 - A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells
AU - Stejerean-Todoran, Ioana
AU - Gimotty, Phyllis A.
AU - Watters, Andrea
AU - Brafford, Patricia
AU - Krepler, Clemens
AU - Godok, Tetiana
AU - Li, Haiyin
AU - del Rio, Zuriñe Bonilla
AU - Zieseniss, Anke
AU - Katschinski, Dörthe M.
AU - Sertel, Sinem M.
AU - Rizzoli, Silvio O.
AU - Garman, Bradley
AU - Nathanson, Katherine L.
AU - Xu, Xiaowei
AU - Chen, Qing
AU - Oswald, Jack H.
AU - Lotem, Michal
AU - Mills, Gordon B.
AU - Davies, Michael A.
AU - Schön, Michael P.
AU - Bogeski, Ivan
AU - Herlyn, Meenhard
AU - Vultur, Adina
N1 - Publisher Copyright:
© The Author(s) 2022.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - 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 nonMBM 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.
AB - 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 nonMBM 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.
KW - brain
KW - melanoma
KW - metastasis
KW - microenvironment
KW - RAC1
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U2 - 10.1093/neuonc/noac212
DO - 10.1093/neuonc/noac212
M3 - Article
C2 - 36054930
AN - SCOPUS:85160251494
SN - 1522-8517
VL - 25
SP - 674
EP - 686
JO - Neuro-oncology
JF - Neuro-oncology
IS - 4
ER -