Preuss Award 121 Leptomeningeal Dissemination Cascade in Medulloblastoma

Abstract

INTRODUCTION: Medulloblastomas (MBs) are a diverse set of tumors in which variation in treatment response is determined by the genes that drive tumor growth. A defining characteristic of MB is leptomeningeal dissemination (LMD) to the brain and spinal cord, which is inversely correlated with survival. We have developed a mouse model as well as in-vitro experiments to further elucidate the LMD cascade. METHODS: We selected ARNT, Eras and RabGDI2 as target genes for our mouse model (n = 80) after a random mutagenesis model implied LMD potential. We also evaluated these candidate genes in-vitro using assays including in-vitro scratch assay with DAOY cells and matrigel chemoinvasion assay with SHH-GNP cells to study their metastatic traits including migration, invasiveness, and proliferation. RESULTS: The in-vivo studies revealed 2 new LMD-promoting genes: ARNT/HIF1ß and RabGDI2. ARNT increased LMD by 6 times and RabGDI by 5 times over the baseline Sonic Hedgehog (SHH) MB model. Also, ARNT was found to be the most potent driver of LMD when compared to all genes evaluated in the past 5 years. The in-vitro studies revealed that ARNT and Eras stimulated migration in the 2 cell lines analyzed. RabGDI2 increased migration of SHH-GNPs only. ARNT and RabGDI2 enhanced invasiveness, but Eras had no effect. No gene stimulated proliferation in either cell lines. These results exemplify the complex interactions, with each gene playing a specific metastatic role, in the LMD cascade. CONCLUSION: We have created a systematic approach to analyzing LMD genes by testing them in-vivo to determine the LMD potential followed by characterizing their specific metastatic role in-vitro. We plan to utilize this in-vivo/in-vitro system to further elucidate genes of the LMD cascade and develop a comprehensive model of the medulloblastoma metastasis.