Abstract Desmosomes are specialized adhesive junctions that link adjacent cells and provide structural integrity in tissues exposed to significant mechanical stress, such as the skin and heart. Disruption of the desmosome adhesion complex is observed in a range of different cutaneous syndromes and during tumor progression. Dysregulation of desmosomal proteins has been associated with enhanced cancer motility, invasion and metastatic potential. Diverse mechanisms for the disruption of desmosome dynamics have been reported, but the specific signaling pathways regulating the expression and localization of desmosome proteins remain elusive. Prior studies have shown that Septin family proteins play an important role in the maintenance and function of adherens junctions and tight junctions. Referred to as the fourth component of the cytoskeleton, Septins are GTP-binding proteins that form oligomeric filamentous structures that associate with cellular membranes and act as scaffolding proteins for a variety of different cellular functions. In particular, Septin-2 has been found adjacent to VE-cadherin containing cell-cell junctions, and loss of Septin-2 disrupts adherens junction structure and barrier integrity in endothelial cells. Septin-9 has also been shown to control adherens junction structure, apico-basal polarity and lumen formation in polarized MDCK cells. In our study, we sought to investigate the importance of Septins in the formation of desmosomal cell-cell adhesions by performing knockdown experiments for Septin-9 in squamous cell carcinoma 9 (SCC9) cells and T47D breast cancer cells. Our experiments show a significant disruption of desmosomal cell-cell junctions in both cancer cell types expressing siRNA specific for Septin-9 (siSept9), in comparison to control siRNA-expressing cells. In particular, border localization of the desmosomal cadherin Desmoglein-2 (Dsg2) and the desmosomal plaque protein Plakophilin-2 were dramatically perturbed in siSept9 cells (determined via immunofluorescence), while the localization of other desmosomal proteins (such as Plakoglobin) remained unaffected. Loss of Dsg2 and PKP2 border staining was not accompanied by changes in total protein expression, suggesting that these changes are predominantly an effect of protein localization. This study has therefore uncovered an important role for Sept9 in maintenance of desmosomal structure in cancer cells, providing insight into mechanisms which may perturb junction structure during cancer progression. Citation Format: Cate G. Lyerly, Zach N. Pierce, Adi Dara Dubash. Defects in junctional localization of desmosomal proteins in cancer cells triggered by loss of Septin-9 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 577.
Lyerly et al. (Fri,) studied this question.