Defining the ground signaling of glioblastoma states

• Applicant: Gaetano Gargiulo, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; General Genetics and Functional Genome Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498514611

Glioblastoma is lethal and no effective treatment was discovered so far. Primary tumors present themselves as a heterogeneous mix of cells with different identities and states. Finding state-specific vulnerabilities to be exploited to selectively kill glioblastoma cells has been proposed but not implemented, at least in part due to a lack of understanding the meaning of individual states for homeostasis and response to treatments. Among the identified glioblastoma states, the most aggressive is the mesenchymal state, which is not connected with the normal brain cell hierarchy and is the predominant entity in patients undergoing standard of care recurrence. This evidence supports that mesenchymal glioblastoma has an adaptive component. We propose to investigate the developmental origin of the glioblastoma states and – to account for the non-autonomous mesenchymal glioblastoma – we will investigate the metabolic routes that support the specification of this state. We will trace the developmental origin of glioblastoma states during mouse embryogenesis to connect developmental identities to transcriptional states by using our recently developed synthetic genetic tracing approach. Moreover, we will profile metabolic changes driven by selected innate immune cells within human glioblastoma initiating cells to characterize how the extrinsic regulation of lipid metabolism modulates glioblastoma states. The role of individual receptor tyrosine kinases and transcription factors in initiating and maintaining glioblastoma identity has been extensively investigated. How these components connect to the cellular origin and the metabolic adaptation underlying tumor progression remains unchartered. This proposal is a fundamental biology proposal to study the molecular basis of glioblastoma states, which will pave the way towards identifying state-selective vulnerabilities.

• DFG Programme: Research Grants