TMOD-11. A NOVEL ANIMAL MODEL OF MEDULLOBLASTOMA METASTASIS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2017-06, Vol.19 (suppl_4), p.iv50-iv50
• Main Authors: Xiang, Chaomei, Baubet, Valérie, Bi, Yingtao, Zhang, Logan, Pal, Sharmistha, O’Rourke, Donald, Martinez-Lage, Maria, Davuluri, Ramana, Dahmane, Nadia
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox083.210

Medulloblastoma, a pediatric malignancy of the cerebellum, has the highest incidence rate among all malignant pediatric brain tumors and remains largely incurable despite the use of aggressive therapies with strong side effects. Medulloblastomas are highly invasive and metastatic, while the molecular and cellular mechanisms underlying these processes are poorly understood. They often metastasize via leptomeningeal dissemination and invade other parts of the brain. One major aim of the aggressive therapies (radiation therapy) in place currently for medulloblastoma is to prevent tumor cells dissemination causing a terrible prognosis on patient survival. We have identified the BTB/POZ and zinc finger domain transcription factor RP58 (aka ZNF238, ZFP238 or ZBTB18) as an essential regulator of brain development. Critically RP58 acts as a suppressor of brain tumor cell growth. Rp58 +/- mice are viable and do not form any visible tumors. To address whether reduced expression of RP58 is involved in medulloblastoma formation and/or progression in vivo, we crossed Ptch1 +/- mice, a genetic mouse model for human SHH medulloblastoma, with Rp58 +/- mice, and found the enhanced incidence and aggressiveness of tumors in the Ptch1 +/- ;Rp58 +/- compound mice. Our analysis indicates that Rp58 heterozygosity in the context of Ptch1 +/- mutation decreases survival and accelerates medulloblastoma formation. In addition, a majority of the Ptch1 +/- ;Rp58 +/- tumors show increased leptomeningeal dissemination, with tumor cells frequently detected at the level of the cerebral cortex or olfactory bulb region, generally not observed in Ptch1 +/- tumors. We have thus generated a novel unpublished mouse model of medulloblastoma metastasis with leptomeningeal dissemination and identified RP58 as a new regulator of medulloblastoma progression in vivo. We will further discuss the cellular and molecular mechanisms regulated by RP58, which may be involved in controlling the dissemination of medulloblastoma cells to other brain regions. In particular, the role of immune cells in this process will be addressed.