Defining the ground signaling of glioblastoma states

• Applicant: Dr. Gaetano Gargiulo
• 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 (GBM) is a highly aggressive and deadly brain cancer, with no curative option. In human tumors, GBM cells exist in different states, with some resembling various neural cell types. However, the origins of these cell states and the mechanisms driving their transitions remain poorly understood. This project aims to address two major questions: 1. Where do glioblastoma cell states come from? o we will use a genetic tool called synthetic locus control regions to track the developmental origins of different GBM cell states in developing mice. o Embryonal tracing will inform mapping GBM identities onto embryonic development and indicate whether these cancer cell states emerge from normal neural development or take on features from other tissues. 2. How does the tumor microenvironment influence glioblastoma plasticity? o We will investigate how microglia (brain immune cells) trigger the transition of GBM cells into a mesenchymal (MES) state, which is more aggressive and resistant to therapy. o A key focus is on how lipid metabolism, particularly myelin-derived lipids, fuels this transition and alters gene activity. This is a focus renewal of the previous project that has generated substantial ground work, including the animal models. Herein, we will integrate spatial proteomics, transcriptomics, and computational modeling to track glioblastoma evolution with high precision. These findings could ultimately pave the way for therapies that target glioblastoma plasticity, making tumors less aggressive and more treatable.

• DFG Programme: Research Grants