Abstract
Abstract Introduction: Metastasis is driven by the migration of cancer cells to different areas of the body, but the mechanisms that induce cell movement are still poorly understood. Aquaporins (AQPs), transmembrane water transport proteins, have been linked to tumor growth, metastasis, and more invasive phenotypes. However, the exact mechanisms behind AQP dysregulation and its role in mediating cancer migration remain unknown. Physical cues and extracellular signals from the tumor microenvironment have been implicated in the progression of cancer; yet the role AQPs play in sensing and signaling have yet to be elucidated. Recent studies have shown the paracrine signaling within the tumor microenvironment is mediated in part by cell secreted extracellular vesicles (EVs). EVs are membrane-delimited nanoparticles capable of protecting and transporting protein and nucleic acid cargo for intercellular communication. EV mediated paracrine signaling has been shown to participate in various steps of tumor progression. Cells are also able to sense complex mechanical signals from the tumor microenvironment to direct more invasive cellular responses. Understanding the role AQPs play in sensing and signaling within the tumor microenvironment can provide a more holistic view of the way AQPs influence cancer progression. Materials and Methods: To study the role of AQP containing EVs and AQPs influence on mechanotransduction to facilitate cancer cell migration, this study has employed 3D in vitro models, including microfluidic devices, to recapitulate relevant in vivo conditions in concert with confocal microscopy to understand cell behaviors. EVs were isolated via tangential flow filtration. AQP levels were down regulated with siRNA complex or upregulated via AQP5-GFP plasmids. Results: Knocking down AQPs with siRNAs, confirmed with western blotting, was shown to reduce cellular migration on 2D surfaces and in confining microenvironments. We have also found that AQPs can enhance the integrin mediated mechanotransduction pathway, which has been implicated in cell proliferation and migration. Effects of integrin mediated mechanotransduction were reversed by suppressing AQP expression. Finally, we have made the exciting discovery that cancer cells secrete extracellular vesicles that contain AQPs. These EVs could be released into the tumor microenvironment to enhance tumor migration. Further work is being conducted to elucidate the AQP-EV relationship. Citation Format: Ian Smith, Allison Moses, Stephanie Kronstadt, Steven Jay, Kimberly Stroka. Role of aquaporins in mechanotransduction and extracellular vesicle-mediated cancer cell communication in complex physical microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 268.
Published Version
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