ED Sciences de la Vie et de la Santé
Study of the Role of NRF2 in the Progression and Metabolic Adaptation of Glioblastoma
by Maya MOUBARAK (Institut de Biochimie et Génétique Cellulaires)
The defense will take place at 9h00 - Conference Room UMR5095 - IBGC - CNRS 33000-Bordeaux
in front of the jury composed of
- Océane MARTIN - Maîtresse de conférences - Université de Bordeaux - Directeur de these
- Elias EL-HABR - Maître de conférences - Sorbonne Université - Rapporteur
- Valerie CORONAS - Professeure des universités - Université de Poitiers - Rapporteur
- Laurence HUC - Directrice de recherche - Université Rennes 1 - Examinateur
Glioblastoma (GB), the most aggressive form of brain tumor, poses substantial therapeutic challenges due to its invasive behavior, treatment resistance, and genetic heterogeneity. Oxidative stress, regulated by Nuclear Factor Erythroid 2-related Factor 2 (NRF2), plays a critical role in cancer progression. NRF2, a central transcription factor for redox homeostasis, exhibits a dual role in cancer, acting as both a tumor suppressor and promoter. This study aimed to clarify NRF2's role in GB development, metabolic adaptation, and therapy resistance using a clinically relevant patient-derived GB model (P3). We employed CRISPR-Cas9 technology to generate NRF2-deficient cell lines and induced NRF2 overexpression to assess its impact on GB biology. Our findings reveal that NRF2 knockout (KO) did not significantly affect P3 sphere growth in vitro, while in vivo experiments demonstrated contrasting tumor growth patterns between the different knockout clones. The tumor of the C7 KO clone exhibited enhanced tumor growth, suggesting a pro-tumoral role for NRF2, while that of C16 KO showed reduced growth, indicating an anti-tumoral effect. Additionally, NRF2 knockout significantly decreased the invasive capacity of GB cells in vitro, but this reduction was not observed in vivo, implying that the tumor microenvironment may modulate NRF2's activity. However, tert-Butylhydroquinone (TBHQ)-induced NRF2 overexpression had no impact on the proliferation or invasiveness of P3 spheres in vitro. Moreover, although NRF2 KO did not alter mitochondrial membrane potential, biogenesis, or protein import machinery, it caused significant metabolic reprogramming. A significant shift toward glycolysis was evidenced by the increased intracellular lactate levels, upregulation of LDHA, and downregulation of LDHB expression, supporting the Warburg effect. Moreover, knocking out NRF2 increased lipid storage by favoring lipid droplet formation. Although NRF2 is known to confer resistance to chemotherapeutic agents like temozolomide (TMZ), our study found that NRF2 knockout did not increase TMZ sensitivity. Unexpectedly, NRF2 deficiency resulted in elevated expression of stemness markers, such as SOX2 and OLIG2, indicating a potential enhancement of stem-like traits, though this did not correlate with the P3 sphere's increased self-renewal capacity. Overall, this study underscores the multifaceted role of NRF2 in GB progression, invasion, and metabolic adaptation. However, future research should explore the underlying mechanisms through which NRF2 influences the molecular pathways and gene networks related to GB progression and metabolism.
ED Sciences Physiques et de l'Ingénieur
Definition of a multi-attribute decision model for the design of social innovations in the renewable energy sector
by Basma SAMIR (ESTIA Recherche)
The defense will take place at 14h00 - Amphi 300 - ESTIA Berri Technopole Izarbel 90 Allée Fauste d'Elhuyar, 64210 Bidart, France
in front of the jury composed of
- Jérémy LEGARDEUR - Professeur - Université de Bordeaux - Directeur de these
- Tatiana REYES - Professeur - Université de Technologie de Troyes - Rapporteur
- Bertrand LARATTE - Professeur - Université Laval - Rapporteur
- Emilie POIRSON - Directrice de recherche - Ecole centrale de Nantes - Examinateur
- Chris MERVEILLE - Docteur - rescoop goiener - Examinateur
In response to current environmental challenges, social innovations have become essential for accelerating the transition to green energy and reshaping energy practices to make them more sustainable. The success of these innovations relies on making multiple decisions and evaluating numerous often competing criteria and objectives. The objective of this thesis, within the framework of the European SocialRes project, is to provide decision-making support for the design of social innovations in this specific sector. To achieve this, a qualitative study was conducted, based on five interviews, to identify the key design factors of social innovations in this sector. The results of this study identified four types of key factors: economic, social, environmental, and participatory. A decision support model incorporating these four types of factors and based on Design Space Exploration was developed. The proposed model first enables decision-makers to construct and visualize the design space by considering the key factors of social innovation in the energy domain. Then, by navigating through this space, it systematically explores different design alternatives to identify the most promising solutions. Finally, it evaluates the selected solution using a set of indicators defined to characterize social innovation in the energy sector: citizen acceptance, project location, economic benefit sharing, and CO2 reduction rate. The proposed model is characterized by a particular consideration of citizen involvement in the decision-making process from the preliminary design phases, assessing their acceptance using Fuzzy logic. The developed model was validated through its application to two cases of social innovations in the energy sector: a photovoltaic self-consumption system and an electric vehicle sharing system. The contributions presented in this thesis assist social innovation designers in the energy sector in making more informed design decisions that are better suited to the needs of users.