Abstract Background: Peritoneal dissemination is a hallmark of advanced ovarian cancer and leading cause of poor patient prognosis. Ovarian cancer metastasis involves adhesion, invasion, and dynamic remodeling of cell-matrix interactions, where integrin trafficking plays a central role. The intracellular sorting receptor, SORL1 regulates receptor recycling and intracellular trafficking, with evidence linking its activity to oncogenic signaling in various cancers. Building on our prior findings that SORL1 modulates endosomal trafficking and recycling of EGFR1 and FGFR4 in ovarian cancer, this study aimed to investigate how SORL1 regulates ovarian cancer invasion and metastasis by modulating integrin trafficking and endosomal recycling. The therapeutic potential of inhibiting tumor peritoneal dissemination and metastasis in recurrent ovarian cancer by targeting SORL1 was also evaluated. Methods: SORL1 expression was knocked down in patient-derived ovarian cancer cells using siRNA/shRNA. Tumor spheroid co-cultured with mesothelial cells were used to quantify cancer cell clearance efficiency. Integrin localization was examined by immunofluorescence co-staining with endosomal markers and confocal microscope imaging. Flow cytometry measured cell surface integrin levels with and without activation by fibronectin as an extracellular matrix ligand. Co-immunoprecipitation and proximity assays assessed SORL1-dependent interactions between integrins α3/β1 and the trafficking adaptor GGA1. Finally, the activity of a SORL1-blocking protein on inhibition of ovarian cancer migration and mesothelial clearance was evaluated. Results: SORL1 knockdown significantly reduced ovarian cancer invasion and mesothelial clearance. Immunofluorescence staining analysis revealed enhanced internalization of integrin-a3 upon SORL1 inhibition, showing a shift from the plasma membrane to intracellular endosomal compartments. Consistently, the decreased surface levels of integrins after fibronectin activation in SORL1-knockdown cells indicated impaired integrin recycling. Increased interaction of integrins with GGA1 in SORL1 knockdown cells suggested accumulation in early and recycling endosomes. SORL1-blocking antibody inhibited ovarian cancer migration and mesothelial clearance. These findings demonstrate that loss of SORL1 disrupts integrin trafficking and surface expression, thereby impairing integrin-mediated adhesion and invasion in ovarian cancer. Conclusion: SORL1 regulates integrin trafficking and recycling to maintain integrin-mediated adhesion and invasion in ovarian cancer cells. Loss of SORL1 disrupts these processes, limiting peritoneal dissemination. Targeting SORL1-dependent trafficking pathways may offer therapeutic potential to inhibit ovarian cancer metastasis. Citation Format: Jasmine Jathan, Viktoriia Kolesnyk, Samantha Goncalves Novo, Miranda Mansolf, Yang Yang-Hartwich, . SORL1 promotes mesothelial clearance and migration of ovarian cancer cells through regulating integrin trafficking abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7486.
Jathan et al. (Fri,) studied this question.