Abstract 583: Septin-9 binds to Desmoglein-2 and controls cell-cell junction strength in cancer cells.

Abstract Septins are a conserved family of GTP-binding cytoskeletal proteins which form oligomeric filamentous structures that play important roles in a wide variety of dynamic cellular processes, including cytokinesis, membrane remodeling and cell migration. Expression of Septins is dysregulated in different tumors, with some isoforms being either upregulated or downregulated, and prior evidence has highlighted a role for several Septins in controlling malignant phenotypes. In particular, Septin-9 is frequently dysregulated in cancer, with genomic amplification at the SEPT9 locus being commonly detected in high-grade carcinomas. Several different mechanisms have been put forth to explain a role for Septin-9 in cancer progression, including control of cell-matrix adhesion, migration and invasion. For example, overexpression of Septin-9 has been shown to enhance extracellular matrix degradation and invasion in breast cancer via recruitment of matrix metalloproteinases. In contrast, less is known about how Septin-9 affects cell-cell junctions, which are also frequently perturbed during cancer progression and metastasis. In our study, we provide evidence that Septin-9 localizes to desmosomal cell-cell junctions in the T47D cancer cell line. Desmosomes have a tripartite organizational structure wherein transmembrane cadherins (Desmoglein and Desmocollin) link adjacent cells, plaque proteins (Plakoglobin and Plakophilin) stabilize arrays of desmosomes on the intracellular face, and a cytoskeletal linker proteins (Desmoplakin) anchors desmosomes to the intermediate filament cytoskeleton. Importantly, we show an interaction between the cadherin Desmoglein-2 and Septin-9 via immunoprecipitation experiments. Loss of Septin-9 does not dramatically perturb mRNA or protein levels of different desmosomal components in T47D cells. Nevertheless, Septin-9 knockdown does result in a statistically significant loss of cell-cell junction strength in squamous cell carcinoma (SCC9) cells (measured via dispase assays), likely as an effect of disrupted localization of desmosomal proteins to cell-cell junctions. Taken together, these studies highlight an important role for Septin-9 in maintenance of desmosome-mediated adhesion in cancer cells. Citation Format: Michael W. Jaber, Emily G. Bernier, Adi Dara Dubash. Septin-9 binds to Desmoglein-2 and controls cell-cell junction strength in cancer cells [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 583.