The Microenvironment of Melanoma Brain Metastasis - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Sivan Izraely-Bino ¹ Orit Sagi-Assif ¹ Shlomit Ben-Menachem ¹ Maya Rappaport-Saban ¹ Moran Frig ¹ Tsipi Meshel ¹ Metsada Pasmanik-Chor ² Roshini Prakash ³ S. Thomas Carmichael ³ Dave S.B. Hoon ⁴ Isaac P. Witz ¹

¹Department of Cell Research and Immunology, Tel Aviv University
²Bioinformatics Unit, Tel Aviv University
³Department of Neurology, University of California Los Angeles
⁴Department of Molecular Oncology, John Wayne Cancer Institute, Saint John’s Health Center

The progression of cancer towards metastasis is driven by autonomous traits of the tumor cells as well as by interactions of tumor cells with non-tumor cells in their vicinity and with soluble factors released by them. Brain metastases occur frequently in melanoma patients with advanced stage disease. Yet, understanding the mechanisms underlying development of brain metastasis is far from complete. Our study aims to uncover these mechanisms and the interactions between melanoma and brain cells.

For our study we have used two experimental systems:

1. We developed human melanoma xenograft models encompassing cutaneous, brain macro-metastatic and brain micro-metastatic melanoma variants, originating from single melanoma tumors. Using these models we identified a set of melanoma brain metastasis signature genes, including Claudin1 (CLDN1). We have found that CLDN1 functions as melanoma brain metastasis inhibitor.

2. Neuro-repair processes occurring after stroke involve microglia, astrocytes and endothelial cells (BECs), and control the localization, survival and differentiation of immature neurons. We hypothesize that melanoma cells utilize post-stroke repair mechanisms for the establishment of brain metastasis. An oxygen-glucose depravation (OGD) treatment of microglia, astrocytes and BECs was used as an in-vitro stroke model. OGD promoted pro-metastatic interactions between brain cells and melanoma, and induced secretion of inflammatory cytokines from brain cells. Inoculation of melanoma cells into mice after transient middle cerebral artery occlusion (MCAO) showed preferential localization of metastatic melanoma cells to areas of tissue regeneration, and recruitment of astrocytes and microglia to metastatic region.

These results demonstrate that brain microenvironment has a crucial role in melanoma brain metastasis formation. Uncovering the involved mechanisms could enable the detection of novel therapeutic targets.

This study was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Needham, MA, USA).