Abstract A13: Functional genomic analysis of central nervous system hemangioblastomas

Hemangioblastomas (HBs) are highly vascular tumors that develop in the Central Nervous System, mainly in the cerebellum, spinal cord and retina. These tumors are usually associated with Von-Hippel Lindau (VHL) disease but they can also appear sporadically. HBs often contribute to the morbidity and mortality of VHL patients due to the location of the tumor and the lack of efficient treatment. The genomic landscape of VHL-associated HBs is underexplored. The tumors develop upon bi-allelic loss of VHL but it is unclear if there are additional oncogenic drivers that influence tumor development. In addition, HBs are highly heterogeneous tumors comprised of diverse cell sub-populations; the origin of the HB tumor cell is controversial. The lack of cell lines and animal models that mimic the disease strongly impairs the research on HB biology and the search for new therapeutic strategies. In order to create an in vitro model to study HB biology, we established tumor-derived cell lines from VHL-associated HB tumors. The cell lines are formed by sub-populations that are morphologically different and express known HB markers such as Podoplanin, VEGFR2 and CXCR4. Moreover, these cells express Hypoxia Inducible Factor 1a (HIF1a), which is stabilized in VHL-deficient cells. We characterized the cell populations corresponding to surface markers expression and we analyzed the signaling pathways of isolated single HB cells derived from human tumors. In addition, we performed next-generation sequencing in HB tumor samples to identify potential oncogenic drivers that contribute to the development of HBs. We found a list of potential hits that we are now confirming with complementary techniques. These data can lead us to the identification of abnormal oncogenic pathways that could be therapeutically targeted in this disease. Finally, we are establishing a zebrafish model that mimics the HB disease. Vhl mutants develop hyper-vascularization in the brain and in the retina which is a common initiation factor in HB development. We are characterizing the vhl brain lesions using transgenic models with labeled vasculature and hematopoietic stem cell compartment. In conclusion, there are no current therapies for HBs and the lack of research models profoundly compromises the research advancement. In this work we established, for the first time, long-term cell lines that can be used to study the disease. The use of next-generation genomics allowed us to dissect the genomic landscape of this tumor type and will allow us to identify the HB cell of origin. All these new genomic data combined with novel resources, including the zebrafish model, will allow us to advance the current knowledge about HBs and may help to identify HB specific therapeutic targets. Citation Format: Ana Martins Metelo, Atanas Kamburov, James Kim, Elizabeth Lockerman, Dana Lee, Frederick Barker, Jeffrey Engelman, Anat Stemmer-Rachamimov, Gad Getz, Othon Iliopoulos. Functional genomic analysis of central nervous system hemangioblastomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A13.