Urothelial Collective-Gliding Response Acts as a Toll-Like Receptor 4–Associated Defense Mechanism

Abstract

Collective cell migration (CCM) is characterized by the coordinated movement of cell groups while maintaining cell-to-cell cohesion. Despite extensive research on CCM, the collective migration of mature epithelial cells over the extracellular matrix in response to external stimuli has not been reported. Using intravital imaging in mice, we identified urothelial CCM (UCCM) triggered by immunogenic substances, including bladder cancer cells (MB49) and uropathogenic Escherichia coli (UPEC). Integrin signaling inhibitors suppress UCCM, significantly enhancing MB49 tumor growth and UPEC bladder infection. UCCM initiation involves Toll-like receptor 4 (TLR4), we designated this TLR4-associated UCCM as the urothelial collective-gliding response (UCGR). Downstream of integrin signaling, urothelial matrix metalloproteinases (MMP)-8 and MMP-9 mediate UCGR. Intravesical instillation of these factors accelerates UCCM and inhibits tumor growth and infection. UCGR may represent a TLR4-associated defense mechanism, offering potential therapeutic strategies for bladder disorders such as refractory cystitis and recurrent non-muscle invasive bladder cancer after endoscopic resection.

Note:
Funding Information: This work was funded by a Grant-in-Aid for Early-Career Scientists from the Japan Society for the Promotion of Science (20K18137 to T. Sano), a GSK Japan Research Grant 2020 (to T. Sano), a JST Moonshot R&D grant (JPMJPS2022 to M. Matsuda), and a Young Researcher Promotion Grant from the Japanese Urological Association (to T. Sano).

Declaration of Interests: The authors have no conflicts of interest to declare.

Ethics Approval Statement: Animal protocols were reviewed and approved by the Animal Care and Use Committee of Kyoto University Graduate School of Medicine Kyoto, Japan (approval numbers: 12064, 13074, 14079, and 15064).