Identifying Genes that Promote Spinal Metastasis in Sonic Hedgehog–Dependent Medulloblastoma in Mice

Keywords: medulloblastoma, animal model, gene, spinal cord neoplasm, metastasis

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     For medulloblastoma patients, short survival times are associated with metastasis of tumor cells via the cerebrospinal fluid to the leptomeninges of the brain and spinal cord or via the bloodstream to extraneural sites.
     Our objective was to identify genes that mediate spinal leptomeningeal metastasis.
     Genetically engineered mice.
     In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas, which rarely metastasize. Mobilization of the Sleeping Beauty transposon in Math1-expressing neuronal precursors in the cerebellum of Patched-deficient mice enhances medulloblastoma formation and leptomeningeal dissemination. Using next-generation sequencing technology, we identified transposon insertion sites in the genome of spinal metastatic tumors. To determine whether these genes directly caused Shh-induced medulloblastomas to metastasize, we overexpressed candidate genes in neural stem cells in the cerebellum of postnatal mice via retroviral transfer in combination with Shh.
     Retroviral transfer of Shh in combination with embryonic stem cell–expressed Ras (Eras) induced spinal leptomeningeal metastasis in 16% of mice whereas Shh alone induced spinal metastasis in just 5% (P=0.04). The Eras gene encodes a membrane-localized protein that is homologous to the Ras oncoproteins and binds and activates the oncogenic signaling enzyme phosphatidylinositol 3-kinase. We will also present results with candidate metastasis genes encoding hepatocyte growth factor, cyclin-dependent kinase-20, and LIM homeobox protein-1.
     This is a mouse study.
     We conclude that Eras promotes spinal leptomeningeal metastasis in Shh-induced medulloblastomas. 
     Also, that medulloblastoma metastasis genes are distinct from those that initiate tumor formation.


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