Myc Confers Aggressive Medulloblastoma Phenotypes By Regulating Cell Migration And Adhesion Genes

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Mechanisms by which Myc confers aggressive phenotypes and adverse outcomes in medulloblastoma remain largely unknown. In this study, we demonstrate using 2 medulloblastoma cell line models that high Myc expression increases cell migration/invasion and induces metastatic orthotopic tumors which recapitulate the aggressive histology of primary anaplastic medulloblastoma. Using ChIP-chip and expression analysis on Myc transformed medulloblastoma cell lines, we identified a subset of cell migration and adhesion genes as direct Myc repressed transcriptional targets. These include ING4, PVRL3, PPAP2B and Tsp-1/THBS1, a potent tumor suppressor not previously implicated in medulloblastoma. Tsp-1 expression in medulloblastoma cell lines and primary tumors were consistently and significantly diminished in the presence of high Myc (n=101, p=0.032). Using ChIP and reporter assays we confirmed Myc and Max co-localization to a basal Tsp-1 promoter and decreased Tsp-1 transcription in the presence of Myc. Our analyses also revealed that JPO2, a Myc interacting protein linked to metastatic medulloblastoma, directly binds the Tsp-1 promoter and augments Myc-mediated Tsp-1 repression. Interestingly, we observed that stable Tsp-1 expression significantly diminished soft agar growth and drastically decreased cell invasion/migration in high-Myc expressing medulloblastoma cell lines without effects on cellular proliferation. Our collective findings highlight a novel and important role for Tsp-1 in Myc- induced metastatic medulloblastoma phenotypes and suggest Tsp-1 agonists may represent attractive, therapeutics for primary metastatic medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3109.