ED Sciences de la Vie et de la Santé
Complementary intra- and extracellular activities of the protein disulfide isomerase AGR2 sustain tumour adaptive capacity and progression
by Marianne GUILBARD (BoRdeaux Institute of onCology)
The defense will take place at 14h00 - Bibliothèque Institut Bergonié, 229 cours de l'Argonne, 33000 Bordeaux, France
in front of the jury composed of
- Fabienne FOUFELLE - Directeur de recherche - Centre de Recherche des Cordeliers (CRC) - INSERM - Rapporteur
- Sabrina KELLOUCHE-GAILLARD - Professeur des universités - CY Cergy Paris Université - Rapporteur
- Pierre SOUBEYRAN - Professeur des universités - praticien hospitalier - Université de Bordeaux - Examinateur
- Eric OGIER-DENIS - Directrice de recherche - Université de Rennes - Examinateur
Tumor cells evolve under chronic stress imposed by sustained proliferation, elevated biosynthetic demand, and persistent perturbations of proteostasis. Central to this adaptation is the endoplasmic reticulum (ER) stress response and its downstream effectors, including protein disulfide isomerases (PDIs). This thesis investigates the role of the PDI family member Anterior Gradient 2 (AGR2) in epithelial cancer, with a particular focus on how its biological functions are shaped by subcellular localization. Integrative analyses of human transcriptomic and proteomic datasets identify AGR2 as one of the most consistently upregulated PDIs across epithelial malignancies, reflecting its close association with secretory stress adaptation. Although AGR2 is canonically described as an ER-resident folding factor, accumulating evidence indicates that it can access the extracellular space and acquire distinct biological activities. Within this framework, our experimental analyses using epithelial ovarian cancer models examine the biological impact of extracellular AGR2 (eAGR2). Functional perturbation of eAGR2 demonstrates a direct contribution to tumor cell behavior, as antibody-mediated neutralization reduces proliferation and migration, whereas exogenous supplementation partially restores these properties, supporting a pro-tumorigenic role for the eAGR2. At the molecular level, quantitative proteomic analyses, complemented by analysis of the TCGA database, indicate that eAGR2 signaling is associated with altered expression of proteins involved in intracellular trafficking and autophagy-related processes. These changes suggest that eAGR2 supports degradative activity and amino acid availability under metabolic stress, thereby sustaining biosynthetic capacity. Consistent with this interpretation, enhanced translational activity is observed in cells exposed to eAGR2. Together, these findings define two distinct yet complementary roles for AGR2. While iAGR2 functions as an endoplasmic reticulum–resident protein disulfide isomerase that promotes protein folding and quality control, eAGR2 acts as an extracellular signal that supports metabolic and translational programs. This dual-compartment organization provides a mechanistic framework in which intracellular and extracellular AGR2 cooperate to reinforce epithelial stress adaptation and promote tumor progression.
ED Sciences Physiques et de l'Ingénieur
Signal integrity analyses of high-speed serial and parallel links for complex mixed-signal boards
by Soazig LE BIHAN (Laboratoire de l'Intégration du Matériau au Système)
The defense will take place at 10h00 - Amphithéâtre Jean-Paul DOM Bât A31, Av. des Facultés, 33600 Pessac
in front of the jury composed of
- Jean-Baptiste BEGUERET - Professeur - Université de Bordeaux - Directeur de these
- Etienne SICARD - Professeur - INSA Toulouse - Rapporteur
- Olivier TESSON - Docteur - NXP - Rapporteur
- Tristan DUBOIS - Associate Professor - Université de bordeaux - CoDirecteur de these
- Marc GATTI - Ingénieur - THALES AVS - Examinateur
- Thierry TARIS - Professeur - Université de Bordeaux - Examinateur
In response to the growing demand for performance, frequency, and data rates that can reach several tens of Gbps, aeronautical products integrate parallel links (DDR) and high-speed serial links (HSSL). These technological developments require a rigorous signal integrity (SI) analysis from the earliest design phases. Thus, PCB technology is becoming more complex in order to meet the constraints of High-Density Interconnect (HDI) circuits, with more layers, increased density, and ever higher data rates. The choice of dielectrics also becomes decisive because their properties vary with frequency, while metallic losses are amplified by the skin effect and copper roughness. Material characteristics must therefore be taken into account during SI analysis for high-speed links, making necessary a design approach based on reliable models and simulations. SI analyses of high-speed signals are essential from the first design steps in order to ensure proper board operation from the initial tests while minimizing manufacturing costs. These simulations are particularly sensitive to even the smallest impedance discontinuities, such as vias and breakout routing of DC-blocking capacitor , IC BGA arrays, and connectors. These simulations require more accurate modeling with 3D electromagnetic models. In order to improve the productivity, flexibility, and robustness of these 3D models of impedance discontinuities, while ensuring their manufacturability and compliance with industrial constraints, these models are parameterized and then coupled with optimization algorithms. However, correlation with measurements is necessary to strengthen confidence in the simulation results and in the selected models and assumptions. Nevertheless, measurement access to the structures of interest is achieved through launches that degrade signal quality. These launches, such as SMA connectors, traces, microvias..., must be removed from the measurement by de-embedding. A test vehicle was manufactured in order to characterize in frequency the impedance discontinuities and high-speed links between different boards, but also to develop techniques for extracting material properties. Finally, the study focuses on the measurement–simulation correlation of DDR links on an avionics board between a controller and its DDR memory. The approach consists of confronting three simulation tools with measurements, relying on a minimally intrusive measurement strategy and on the analysis of eye diagrams and timing parameters. This work makes it possible to show the advantages of relying more on simulations and to validate their results in order to reduce design cycles.