The role of LIN28A in brain development and pediatric brain tumors

• Applicant: Professorin Dr. Julia Neumann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416054672

The highly preserved protein LIN28A is important for (embryonal) stem- and precursor cells. LIN28A is also reported as a multifunctional oncogene in a variety of extracranial brain tumors. High levels of LIN28A were found to be correlated with more undifferentiated tumors and a worse survival of patients. Brain tumors, that are believed to arise from embryonal/undifferentiated cells, are the so called embryonal brain tumors and the intracranial germ cell tumors. Of these, embryonal tumors account for the most common malignant solid tumors in childhood. Embryonal brain tumors with multilayered rosettes (ETMRs) and atypical teratoid/rhabdoid tumors (AT/RTs) belong to the group of embryonal brain tumors. These are highly malignant tumors and patients usually survive less than one year. Intracranial germ cell tumors are predominantly found in children and adolescents and show a variable prognosis that is dependent on histological subtype. ETMRs, AT/RTs and intracranial germ cell tumors are characterized by a high expression of LIN28A, that is not found in other pediatric brain tumor entities. However, barely anything is known about the function of LIN28A in brain development and its role in ETMRs, AT/RTs and intracranial germ cell tumors. The aim of the presented research project is to analyze the role of LIN28A during brain development and to analyze its significance for the development of ETMRs, AT/RTs and intracranial germ cell tumors. Therefore, Lin28A shall be overexpressed and downregulated during murine brain development in vivo. Effects on brain morphology, mRNA, miRNA and the proteome will be studied. In order to analyze the function of LIN28A in brain tumors, its expression will be correlated with clinical and molecular parameters in human ETMRs, AT/RTs and germ cell tumors. In order to analyze Lin28A during tumor formation in vivo, tumor mouse models that rely on an overexpression of Lin28A will be developed for these brain tumor entities. Grown tumors will be molecularly analyzed to detect target structures of Lin28A. Finally these structures (proteins, mRNA, miRNA) will be validated in functional in vitro assays. The results shall elucidate entity specific or comprehensive therapeutic targets in tumors with high LIN28A expression in order to develop targeted therapies.

• DFG Programme: Independent Junior Research Groups