Deciphering spatial cellular heterogeneity in glioblastoma

• Applicant: Dr. Rouven Höfflin
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495418889

The diversity of cancer cells within an individual tumor (intra-tumoral heterogeneity, ITH) has been identified among a variety of cancer types and greatly affects various aspects of tumor biology, such as malignant progression, therapy resistance and metastasis. Elucidating the causes and consequences of ITH is therefore of utmost importance for the development of new treatment strategies.Novel single-cell sequencing technologies are powerful tools to study ITH at the genomic or transcriptomic level, the latter enabling the investigation of ITH at several distinct layers: (i) expression profiles of benign cells from the tumor microenvironment, (ii) genomic influenced and iii) non-genomic influenced transcriptional states of cancer cells. Single-cell RNA-sequencing has been extensively applied in glioblastoma, the most common and aggressive brain tumor. The transcriptomic data led to the identification of four distinct cellular states that are referred to as i) astrocyte-like, ii) oligodendrocyte progenitor cell-like, iii) neural progenitor cell-like, and iv) mesenchymal-like glioblastoma cancer cells. However, the spatial distribution of these subpopulations within the tumor remains largely unknown. The crosstalk of each individual cancer cell with the tumor microenvironment might influence its transcriptomic state and could elucidate potential targets for cell state-specific therapy. To address this hypothesis, we intend to use novel transcriptomic technologies providing detailed spatial resolution on tumor samples of glioblastoma patients.Current treatment modalities for glioblastoma – including complete resection of the primary tumor, irradiation and chemotherapy – consistently fail due to local or distant tumor relapse. The characteristics of the responsible cancer cells, which have the capacity to invade the brain parenchyma even before initiation of therapy, remain unknown. We therefore aim to define their transcriptomic cellular states (see above) and to investigate associated vulnerabilities using single-cell technologies on various invasive glioblastoma mouse models.The ultimate goal is to use the knowledge of the spatial organization of glioblastoma cells and the characterisation of their invasive subtypes to develop better and personalized cancer treatments.

• DFG Programme: WBP Fellowship
• International Connection: Israel
• Host: Dr. Itay Tirosh