Targeting Gangliosides for Melanoma Brain Metastasis Treatment

In vitro three-dimensional analysis elucidates the role of cell surface GD3 ganglioside and ST8SIA1 in melanoma brain metastasis.

John Wayne Cancer Institute (JWCI), Fudan University, Providence St. Joseph Health Center, Tel-Aviv University, The University of Texas MD Anderson Cancer Center, Oregon Health and Science University (OHSU) Knight Cancer Institute Portland

Romela Irene Ramos, Matias A. Bustos, Jinfeng Wu*, Peter Jones, Shu Ching Chang, Eiji Kiyohara, Kevin Tran, Xiaoqing Zhang, Stacey L. Stern, Sivan Izraely, Orit Sagi-Assif, Isaac P. Witz, Michael A. Davies, Gordon B. Mills, Daniel F. Kelly, Reiko F. Irie, and Dave S. B. Hoon*

3D tissue model for drug screening

Disease model:
Melanoma metastasis

Cell types:
melanocytes, lymph node metastasis (LNM) and melanoma brain metastasis (MBM) cells

VitroGel® 3D (TWG001)

Melanoma or skin cancer is an aggressive type of cancer and its occurrence is becoming increasingly common worldwide. It is known for its susceptibility to metastasize to multiple organs which results in poor prognosis. One of the most frequent causes of extracranial brain tumors is due to melanoma metastasis to the brain. Melanoma Brain Metastasis (MBM) is still a major clinical problem with minimal treatment options. While identifying the factors involved in MBM progression, it was found that there was no genomic mutation or epigenomic aberration that was associated with the development of MBM. This further elucidated the involvement of a more complex mechanism. GM3 and GD3 are the most dominant cell surface ganglioside in human cutaneous melanomas. It has been studied that GD3 is known to promote tumor migration and angiogenesis. GD3 synthase or ST8SIA1 is a sialyltransferase that converts GM3 to GD3. Based on the observation that ganglioside metabolism is significantly changed during melanoma progression to MBM, it implies the role of specific ganglioside pathways that promotes metastasis. Romela Ramos and colleagues have hypothesized that ST8SIA1 plays a role in MBM development by promoting GD3 phenotypic expression though the activation of the canonical NF-jB pathway.

Icaritin, an herbal medicine extract from the plant Herba epimedeii, has been identified as a potential inhibitor of ST8SIA1 expression. Icaritin has the potential to suppress melanoma growth and regulate fatty acid of the cell membranes. Therefore, the regulatory role of icaritin in ganglioside synthesis in melanoma cells was investigated. It was found that icaritin targets particularly high GD3 expressing MBM cells and downregulates ST8SIA1, by decreasing the canonical NF-jB pathway activation, resulting in reduced cell growth and colony cell formation. An important finding of the study was that ST8SIA1 upregulation promotes GD3 expression in MBMs and may play a role in MBM development and progression. In addition, ST8SIA1 seemed to have a variable expression in lymph node metastasis (LNM). However, when ST8SIA1 expression is enhanced in LNM it is associated with poor prognosis.

Researchers used Vitrogel 3D, a pure hydrogel matrix system, to mimic tumor environment and study the effects of icaritin on cell proliferation in 3D cell culture. It has been proven that 3D culture systems are more reflective of the in vivo cellular responses due to the presence of cellular communication and development of extracellular matrix. Important differences in ganglioside phenotype of melanoma were observed in 2D and 3D cultures, whereby 3D culture significantly had developed enhanced GD3 levels for GD3 low-expressing metastatic cells. Furthermore, activation of ST8SIA1 was noted in the 3D culture. This may be explained by the correlation of GD3 with stronger extracellular matrix (ECM) adhesion and focal adhesion kinase tyrosine phosphorylation. In 3D cell culture, icaritin was effective in suppressing cell proliferation in both MBM and LNM cells.

This study demonstrated that GD3 levels and ST8SIA1 expression are upregulated in 3D in vitro model, presenting ST8SIA1 as a theranostic target for MBM treatment.

Read the publication:

Ramos, R. I., Bustos, M. A., Wu, J., Jones, P., Chang, S. C., Kiyohara, E., Tran, K., Zhang, X., Stern, S. L., Izraely, S., Sagi‐Assif, O., Witz, I. P., Davies, M. A., Mills, G. B., Kelly, D. F., Irie, R. F., & Hoon, D. S. B. (2020). Upregulation of cell surface GD3 ganglioside phenotype is associated with human melanoma brain metastasis. Molecular Oncology.

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