ED Sciences de la Vie et de la Santé
Characterisation and role of lipid droplet catabolism in glioblastoma
by Cloe TESSIER (BoRdeaux Institute of onCology)
The defense will take place at 14h00 - Amphithéâtre de l'IECB 2 Rue Robert Escarpit 33607 PESSAC
in front of the jury composed of
- Lucie BRISSON - Chargée de recherche - Université de Bordeaux - Directeur de these
- Claire PECQUEUR - Directrice de recherche - CRCI2NA - Rapporteur
- Dominique DELMAS - Professeur - Center for Translational and Molecular Medicine. - Rapporteur
- Pierre-Damien DENECHAUD - Chargé de recherche - Institut des Maladies Métaboliques et Cardiovasculaires, I2MC - Examinateur
- Thierry VIROLLE - Directeur de recherche - Institut de Biologie Valrose (iBV) - Examinateur
- Francesca GIORDANO - Directrice de recherche - Institute for Integrative Biology of the Cell - Examinateur
Glioblastomas are the most common and aggressive primary brain tumors in adults. Current therapies show low efficacy, primarily due to the high resistance of glioblastoma cells to treatment, their significant ability to invade healthy brain tissue, and a high degree of intra- and inter-tumor heterogeneity. Within a single tumor, multiple molecular subtypes, cellular states, and levels of differentiation coexist. Furthermore, several metabolic subtypes have been identified, leading to a strong ability of glioblastoma cells to utilize different metabolic substrates to survive and invade. This metabolic plasticity, which consists of the adaptation of intracellular pathways to utilize available substrates, contributes to their accommodation into the microenvironment. Heterogeneity and metabolic plasticity represent an attractive therapeutic target in glioblastomas. Lipid droplets, through their ability to store and release lipids depending on the microenvironment conditions, may contribute to the metabolic plasticity of glioblastomas. The objective of this work is therefore to propose new strategies to target the heterogeneity and metabolic plasticity established in glioblastomas. Using a co-culture model involving cerebroïds and glioblastoma cells, as well as in vivo models, we demonstrate in this study that lipid droplets are distributed heterogeneously within glioblastomas. They are found to be enriched in the center compared to the periphery and healthy tissue, and their degradation cycle is highly dynamic. We demonstrate that in glioblastoma cells, HSL lipase participates in the degradation of lipid droplets into free fatty acids, which then serve as substrates in β-oxidation for energy production. This lipid transfer is facilitated by the proximity between lipid droplets and mitochondria. This energy source derived from lipid droplets promotes cell proliferation, invasion, and tumor growth. Indeed, we demonstrate that when lipid droplet breakdown is inhibited, tumor growth is reduced, while at the same time increased oxidative stress is observed, which is associated with enhanced sensitivity of glioblastoma cells to chemotherapy. Overall, our work demonstrates the role of lipid mobilization via HSL lipase in the metabolic plasticity and aggressiveness of glioblastomas, which could represent a new therapeutic strategy. The metabolic aspect of the project led us to develop a protocol to study the oxygen consumption of glioblastoma stem cells cultured in spheroids. Finally, since one of the roles of fatty acids is to serve as an energy source for mitochondria, we also investigated the potential of directly targeting the mitochondrial respiratory chain. Our results showed that the molecule mubritinib, by inhibiting complex I of the respiratory chain, reduces the proliferation and stem cell phenotype of glioblastoma cells and inhibits tumor growth, while being non-toxic to animals. Taken together, these results demonstrate that targeting the metabolism of glioblastoma cells, and particularly the components involved in adaptation, including lipid droplets, is a strategy that yields positive results. Furthermore, targeting lipids may be particularly relevant because it affects not only metabolism but also components essential to membrane composition and cellular signaling. These findings are currently driving the development of new therapeutic strategies to target HSL.
ED Sociétés, Politique, Santé Publique
Memory and lexical access: organization and role of semantic features in young and older adults
by Widad RACHDI (Laboratoire de Psychologie)
The defense will take place at 14h00 - Amphithéâtre Pitres 3ter Pl. de la Victoire, 33000 Bordeaux
in front of the jury composed of
- Christelle ROBERT - Professeure des universités - Université de Bordeaux - Directeur de these
- Laurence TACONNAT - Professeure des universités - Université de Tours - Rapporteur
- Liliana RICO DUARTE - Professeure des universités - Université Toulouse Jean Jaurès - Rapporteur
- Manuel GIMENES - Maître de conférences - Université de Poitiers - Examinateur
- Stéphanie MATHEY - Professeure des universités - Université de Bordeaux - CoDirecteur de these
Semantic features are the attributes associated with words (e.g., dog,
, ). The general aim of this thesis was to characterize the nature and organization of semantic features for a set of French words, and to evaluate their role in word identification and word recall in both young and older adults. Six studies were conducted in total. First, we collected semantic features for 360 concepts using a feature generation task with young adults aged 18 to 25 (Study 1). Subsequently, Study 2 evaluated the predictive power of the number of semantic features derived from Study 1 through a virtual study conducted on lexical decision data from young adults. Study 3, conducted in a laboratory, examined the effect of the number of semantic features, manipulated via a factorial design, on visual word recognition in young adults (18-25 years) and older adults (60 years and older). Studies 4 and 5 aimed to examine the influence of the number of semantic features on word recall in these two age groups using free recall tasks. The last study was dedicated to collecting features produced by older adults aged 60 and over (Study 6). Study 1 enabled the development of a feature production norm for young adults, including several indicators for concepts and features. We then demonstrated that the number of semantic features predicted lexical decision performance in young adults (Study 2) and facilitated this performance in both young and older adults (Study 3). This facilitating effect was, however, more marked in the former group than the latter (Study 3). In the free recall task, when list composition was controlled, a facilitating effect of the number of semantic features was observed in immediate free recall (Studies 4 and 5), but not in delayed recall (Study 5). This effect was modulated neither by age (Studies 4 and 5) nor by learning strategies (Study 4). Finally, in Study 6, a production norm was developed with older adults to provide semantic metrics comparable to those in Study 1. A comparison of the two norms revealed that the nature and organization of semantic features differed by age group: features were less shared among older participants, less correlated, more distinctive, and more taxonomic in nature. Conceptual networks appeared to be less structured, less efficient, and less connected in older adults (Study 6). Overall, semantic features constitute a relevant indicator for studying semantic knowledge in adults across different ages. By allowing for a fine-grained analysis of semantic knowledge, they represent a cross-cutting concept relevant to both network models and feature-based approaches to semantic memory. The results are discussed in line with models of semantic memory, word identification, and memory. Several research avenues are proposed to further investigate the nature and organization of semantic features and their role in young and older adults.