A Distinct Pattern of Growth and RAC1 Signaling in Melanoma Brain Metastasis Cells

Authors

Ioana Stejerean-Todoran
Phyllis A Gimotty
Andrea Watters
Patricia Brafford
Clemens Krepler
Tetiana Godok
Haiyin Li
Zuriñe Bonilla Del Rio
Anke Zieseniss
Dörthe M Katschinski
Sinem M Sertel
Silvio O Rizzoli
Bradley Garman
Katherine L Nathanson
Xiaowei Xu
Qing Chen
Jack H Oswald
Michal Lotem
Gordon B Mills
Michael A Davies
Michael P Schön
Ivan Bogeski
Meenhard Herlyn
Adina Vultur

Publication Date

4-6-2023

Journal

Neuro-Oncology

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 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.

Keywords

Humans, Prognosis, Melanoma, Skin Neoplasms, Brain Neoplasms, Biomarkers, Tumor Microenvironment, rac1 GTP-Binding Protein, brain, melanoma, metastasis, microenvironment, RAC1

DOI

10.1093/neuonc/noac212

PMID

36054930

PMCID

PMC10076948

PubMedCentral® Posted Date

9-2-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes