Mechanisms and clinical implications of intratumoral heterogeneity in PFA ependymoma

• Applicants: Professor Dr. Kornelius Kerl; Professor Dr. Ulrich Schüller
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527532822

Ependymomas are among the most malignant tumors of childhood and, in children, usually arise in the posterior fossa. The biology of the tumors is largely unknown, and many children die from this disease, especially if the tumor belongs to the EPN-PFA (ependymoma of the posterior fossa, subtype A) subgroup. Preliminary work on this project has shown that EPN-PFA probably exhibit a previously poorly described, but particularly high degree of intratumoral heterogeneity. Simply looking through the microscope reveals large morphological differences in different tumor regions. Extensive molecular analyses in preparation for this project have also shown that genetic and epigenetic features vary greatly between tumor sites, including, for example, chromosomal alterations, which are thought to have high prognostic significance. Finally, we were able to show in initial single cell analyses that tumors are not only composed of distinct differentiated tumor cells, but also harbor numerous immune cells that communicate with the tumor cells. The initial goal of the project is to precisely describe the intratumoral heterogeneity of EPN-PFA in a large series of human tumor samples at the morphological, genetic, epigenetic, and transcriptional levels and to evaluate its clinical significance. In a next step, organoids will be used, which has been established in preliminary work. These are three-dimensional structures that grow in the cell culture dish and contain organ-like brain structures as well as tumor cells that infiltrate normal tissue and proliferate therein. With these organoids, not only the development of tumor heterogeneity can be observed and understood in great detail, but also the interaction between tumor cells and tumor-infiltrating immune cells can be studied. Subsequently, the tumor organoids will be treated with common chemotherapeutic agents to explore which tumor cell areas and populations are chemosensitive and which are resistant. In addition, we will eventually examine the extent to which the interaction of tumor cells and immune cells affects the efficacy of chemotherapeutic agents. In summary, this project will not only study the biology of EPN-PFA in more detail. Rather, novel in vitro models will also be used to identify mechanisms of chemoresistance that will lead to the development of new therapeutic strategies for patients with EPN-PFA in the future.

• DFG Programme: Research Grants