PTPS-02FOXR2: AN ONCOGENE IN MEDULLOBLASTOMA

Medulloblastoma is the most common malignant brain tumor in children. There continues to be significant morbidity associated with current therapy, which includes surgery, chemotherapy and radiation. More knowledge about drivers of this tumor will allow development of more targeted therapies. Our lab has previously identified FOXR2 as a driver for MB using Sleeping Beauty insertional mutagenesis. We have begun to examine the role of FOXR2 in the role of medulloblastoma formation by over expression and transcription activator like effector nuclease mediated knock-out in cellular models, RNA sequencing and reverse phase protein array (RPPA) of these cells, and allograft mouse models. Overexpression of FOXR2 in a non-tumor forming, immortalized mouse cerebellar cell line (C17.2) results in significantly increased soft agar colony formation but no differences in proliferation. This is similar to the Koso et al, 2014 findings that examined the effects of FOXR2 overexpression in granule neuron progenitor cells. RNA sequencing of the C17.2 cells with foxr2 overexpression have identified upstream regulators which are activated such as HIF1A, IFG1, TP53, ERRB and MYC that have previously been identified to be upregulated in medulloblastoma. The exact mechanism of FOXR2 has yet to be elucidated and additional RNA sequencing of the knock out cell lines in comparison to the wild type will be conducted to further our understanding. RPPA has also been completed and analysis is being carried out currently. In addition to our in vitro findings we have examined the level of expression of 45 human medulloblastoma samples via staining of tissue microarray and from those samples there appears to be a subset of patients in the SHH subgroup which express FOXR2 at high levels. Our findings support that FOXR2 is an oncogene in a number of patients with SHH subtype medulloblastoma and may be a target for development of therapeutic targets.