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Functional genetic characterization of a mouse model of Glioma

Final Report Summary - FGCMOG (Functional genetic characterization of a mouse model of Glioma)

Malignant Glioma is the most common brain cancer in adults, and it has seen very limited therapeutic advances over the last decades. This is largely due to: i) limitation to surgical resection, ii) our limited understanding of brain tissue homeostasis, and of the molecular mechanisms of tumor initiation and maintenance, which could be exploited to design targeted therapies. Genetic evidences showed that Bmi1 - a transcriptional regulator that belong to the Polycomb group Proteins – is essential to adult stem cells maintenance and to tissue-related neoplasia.
The aim of this project as outlined in the original application is the elucidation of molecular mechanisms required for adult neural progenitor and malignant glioma cells self-renewal. To this end, we dissected the regulatory network of Bmi1 by using cutting-edge high-throughput technologies to identify Bmi1 downstream genes, and to ablate their function in vivo, in a mouse model for glioma.
During this project, we have analyzed mouse in primary mouse and human neural progenitor NPCs) and glioblastoma “stem-like” cells GSCs), and we identified mediators of Bmi1 activity by combining high-throughput chromatin- immunoprecipitation with in vivo RNAi screening. This experimental approach led us to conclude that:
1) Bmi1 is important to coordinate the appropriate transcriptional response in adult mouse neural progenitor cells exposed to critical regulators of brain homeostasis such as Tgf-β/BMP agonists, or to general factors inducing adult stem cell differentiation such as those contained in the bovine serum.
2) Bmi1 direct target gene Atf3 is tumor suppressor gene in brain tumors, and directly inhibits key oncogenic pathways in glioblastoma stem cells.