Description:
<jats:title>Abstract</jats:title>
<jats:p>Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.</jats:p>