Identification and targeting of key oncogenic drivers in pediatric and adult H3K27M-gliomas at the single-cell level

• Applicant: Dr. Ilon Liu
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416701173

Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) present a recently defined, invariably fatal molecular entity of high grade gliomas, that are found primarily in children, but are also increasingly recognized in adults, with a median survival of 9-12 months in both pediatric and adult tumors. Recent advances in single-cell RNA-sequencing have been pioneered by Professor Mariella Filbin of Harvard University in pediatric H3K27M-gliomas to dissect the tumors’ cellular architecture, revealing a developmental hierarchy and key transcriptional drivers of the putative tumor-driving glioma stem cells. While pediatric H3K27M-gliomas have now been well characterized on the molecular and cellular level, this is yet to be done in adult tumors to elucidate whether they share the same molecular and cellular characteristics as their pediatric counterparts. The goal of this project is to characterize the so far uncharted cellular and transcriptional architecture of adult H3K27M-gliomas by single-cell RNA-sequencing, and to functionally validate specific transcriptional and oncogenic drivers in both the pediatric and adult tumors by CRISPR/Cas9-mediated in vitro and in vivo knockout screens. To dissect the transcriptional profile of the tumors’ microenvironment and the putative cancer stem cell niches, single-cell RNA-sequencing will be complemented by applying spatial transcriptomic technologies to the pediatric and adult tumors in situ. The proposed project will pave the way to develop novel therapeutics targeting the specific cellular architecture of these devastating tumors.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Mariella Filbin