Data from <i>Sleeping Beauty</i> Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Abstract

<div>Abstract<p>Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using <i>Sleeping Beauty</i> (<i>SB</i>) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified <i>SB</i>-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with <i>FOXR2</i> activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including <i>Arhgap36, Megf10</i>, and <i>Foxr2</i>. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis <i>in vitro</i> and <i>in vivo</i>. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET.</p>Significance:<p>A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.</p></div>