THESIS DEFENSE - Federico DI MODUGNO

Federico Di MODUGNO

PhD candidate in UMR INSERM U1242 Oncogenesis Stress Signaling - PLATON Team

“ER stress-mediated expression of AGR2 confers aggressive features to intrahepatic cholangiocarcinoma”

Abstract:
Anterior Gradient 2 (AGR2) is a protein within the disulfide isomerase (PDI) family that plays a key role in the endoplasmic reticulum (ER) stress response and protein quality control. AGR2 is overexpressed in several cancers, including lung, breast, and colon, and its presence is typically associated with increased tumor aggressiveness and metastatic potential, particularly through the Epithelial to Mesenchymal Transition (EMT). However, the mechanisms by which AGR2 drives these processes remain poorly understood. In this study, we investigate the role of AGR2 in Intrahepatic Cholangiocarcinoma (iCCA), a highly aggressive cancer originating in the bile ducts. Due to late-stage diagnosis and early metastasis, surgical resection, the primary treatment, is rarely feasible. iCCA can be classified into proliferative and inflammatory subtypes based on gene expression profiles. Our analysis reveals that AGR2 overexpression is significantly associated with the proliferative subtype and correlates with reduced overall survival in iCCA patients. To further elucidate AGR2's role, we explored its regulatory mechanisms and its impact on cell phenotypes, including proliferation and migration. We generated a stable AGR2-silenced iCCA cell line and conducted in vivo studies, demonstrating that AGR2 inhibition drastically reduces metastatic potential. These findings suggest that AGR2 is a critical driver of iCCA progression and a potential therapeutic target.