Deciphering the biology of myxopapillary ependymomas

• Applicant: Professor Dr. Ulrich Schüller
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462470667

The classification of CNS tumors is traditionally based on histological features. Novel approaches include global DNA methylation profiling as a very reliable tool to identify biologically and clinically distinct brain tumor entities and subgroups. Still, until today, both the histological and the epigenetic definition of myxopapillary ependymoma (MPE) include cases with a long-term progression-free survival (PFS) as well as cases with early relapse and metastatic spread. Also, molecular tumor drivers or tumor markers are totally unknown for this entity. Therefore, the overall aim of the project is a robust, clinically relevant classification system, an in-depth biological understanding, and the development of appropriate model systems for MPE. Preliminary work on a smaller series of cases has identified the transcription factor HOXB13 to be strongly positive in all analyzed MPE, but not in other spinal cord neoplasms. HOXB13 might therefore serve as a potent marker and suggests HOXB13-positive cells in the spinal cord as potential cells of tumor origin. Furthermore, our data point towards two distinct subgroups of MPE that display significant differences in age, MGMT promoter methylation, global DNA methylation, morphology and PFS.In the first step of this project, we will extend our cohort to a total number of 200 epigenetically defined MPE. Apart from global DNA methylation profiling, our analyses will include MGMT promoter methylation, detailed morphology, marker expression, copy number alterations as well as detailed clinical annotations. We will then use these data to thoroughly describe multidimentional tumor characteristics, to define biologically distinct tumor subgroups and to determine their clinical meaning. Next, a subset of tumors will additionally undergo RNA and whole exome sequencing in order to identify potential tumor drivers and to understand global gene expression and signaling pathways. The exact frequency of the most abundant recurrent alterations will then be confirmed by targeted approaches in the entire series of 200 MPE. Finally, we will functionally validate potential tumor drivers in vitro and in vivo. Primary cultures will be established from precursor cells of the lumbar spinal cord of Hoxb13-cre::lslRFP mice. Such cells, which can easily be recognized and enriched through their RFP expression, will then be manipulated by lentiviral constructs in order to overexpress potential tumor drivers, deplete potential tumor suppressors, and confirm their growth in vivo.Together, results from this project shall enable clinicians to more accurately predict the potential need for close surveillance and adjuvant therapy. Moreover, novel model systems based on newly identified tumor-driving genetic alterations will allow advanced understanding of tumor growth as well as preclinical studies aiming at the targeted prevention or therapy of tumor relapse and metastatic spread.

• DFG Programme: Research Grants