Upregulation of Cell Surface GD3 Ganglioside Phenotype is Associated with Human Melanoma Brain Metastasis.

Publication Title

Mol Oncol

Authors

Romela Irene Ramos, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USAFollow
Matias Bustos, Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow
Jinfeng Wu
Peter Jones, Dept of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.Follow
Shu-Ching Chang, Department of Biostatistics, Medical Data Research Center at Providence Health and Services Center, Portland, OR, USAFollow
Eiji Kiyohara, Dept of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
Kevin Tran, Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow
Xiaoqing Zhang, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa MonicaFollow
Stacey L Stern
Sivan Izraely
Orit Sagi-Assif
Isaac P Witz
Michael A Davies
Gordon B Mills
Daniel F Kelly
Reiko F Irie, Dept of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Santa Monica, CA, USA.
Dave S B Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Pacific Neuroscience Institute, Saint John's Health Center, Providence Health Systems, Santa Monica, CA, 90404, USAFollow

Document Type

Article

Publication Date

5-2-2020

Abstract

Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM) development. We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA-ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (n=23), LNM and visceral metastasis (n=45), and MBM (n=39). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well-annotated melanoma patients from multicenters with AJCC stage III B-D LNM (n=58) with 14 year follow-up. High ST8SIA1 expression was significantly associated with poor overall survival (HR=3.24; 95% CI, 1.19-8.86, p=0.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development; hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation whereby, ST8SIA1 knockdown had opposite effects. Icaritin, a plant-derived phytoestrogen treatment significantly inhibited cell growth in high GD3 positive MBM cells through targeting the canonical NFκB-pathway. The study demonstrates GD3 phenotype associates with melanoma progression and poor outcome.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology