Deciphering cellular interaction between malignant and normal brain cells in pediatric high-grade gliomas

• Applicant: Dr. Sina Neyazi
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508230354

Pediatric central nervous system (CNS) tumors are the most common solid tumors and the leading cause of cancer related death in childhood. Pediatric high-grade gliomas (pHGG) are a group of aggressive brain tumors, including diffuse midline gliomas (DMG), that have a poor prognosis with a median survival of only a few months. In recent years, immense progress has been achieved in deciphering the underlying genetic alterations in pHGG. For instance, mutations in lysine 27 of the histone 3 gene (H3K27M) and in glycine 34 of the histone 3 gene (H3G34) have been identified as important oncogenic mutations in the development of pHGG. However, efforts to translate these findings into new therapeutic options have not yet been successful. It is now hypothesized that, in addition to the known genetic alterations, other factors might also have an influence on the development and growth of pHGG. The spatial and temporal developmental origin of pHGG as well as the cellular heterogeneity and developmental hierarchy within a tumor might shape the aggressive biological behavior of pHGG, too. Moreover, recent findings indicate that the normal tumor microenvironment is another essential factor in the pathogenesis of pHGG. Therefore, the aim of this project is to decipher cellular interactions between malignant pHGG cells and normal brain cells. Our existing single-cell RNA sequencing (scRNA-seq) dataset of 80 pHGG will be used to identify potentially interacting normal and malignant cellular subpopulations using PciSeq, a spatially resolved transcriptomic method. In the next step, relevant cellular interactions, such as upregulated receptor-ligand pairs, will be derived from the scRNA-seq data of these neighboring, potentially interacting cell populations. In the final step of the project, these cell-cell interactions between normal brain cells and malignant pHGG cells will be functionally analyzed in human brain organoids, in which freshly obtained human pHGG cells are fused with brain organoids containing normal brain cells of different developmental stages. The aim of this highly innovative project is to elucidate the influence of normal brain cells on the pathogenesis of pHGG for the first time. The identified cell-cell interactions between normal and malignant cells might serve as promising targets for the development of new therapeutic options against this lethal disease in children.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Mariella Filbin