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Nesprin-1/2 facilitates breast cancer cell pore migration via nucleus deformation

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Abstract

The dissemination of cancer cells is one of the main reasons for treatment failure. During the process of establishing distant metastases, cancer cells must migrate through narrow environments, such as intercellular junctions, extracellular matrix, and basement membranes. The deformability of the cell nucleus is a limiting factor for migration through narrow environments; therefore, as the largest and hardest organelle, the nucleus is a key factor in crossing restrictive spaces. Nesprin-1/2 provides mechanical linkage between the nucleus and the cytoskeleton, but the specific mechanism by Nesprin-1/2 regulating tumor cell nuclear deformation is unclear. Our study found that knocking down Nesprin-1/2 significantly weakens cell migration ability, and knocking down Nesprin-1/2 makes the nucleus becoming more easily deformed. Meanwhile, the knockdown of Nesprin-1/2 leads to a decrease in Lamin A/C levels. To explore whether Lamin A/C protein undergoes degradation, we treated cells with caspase-6 inhibitor Z-VEID-FMK, autophagy inhibitor 3-methyladenine (3-MA), or broad-spectrum proteasome inhibitor MG132, and found that knockdown of Nesprin-1/2 led to the degradation of Lamin A/C via the proteasome pathway. Through immunofluorescence experiments, we observed F-actin distribution in the process of pore migration, and found that knockdown of Nesprin-1/2 weakened the pushing force of the nuclear tail, making it unable to propel the nucleus forward. In conclusion, this study demonstrates that Nesprin-1/2 regulates nuclear deformation and reorganizes the cytoskeleton, which together affects cell pore migration and provides a theoretical reference for the study of nuclear deformation mechanisms.

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Acknowledgements

This work is supported, in part or in whole, by the National Natural Science Foundation of China (32071304, U19A2006, 12132004, 11972111, 32171309, 12272086), the China Postdoctoral Science Foundation (2019T120821), the Sichuan Science and Technology Program (2023NSFSC1233, 2022NSFSC0048, 2022NSFSC0686, 2023YFSY0038), and the Joint Funds of Center for Engineering Medicine (ZYGX2021YGLH017).

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Authors and Affiliations

  1. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China

    Xiang Qin, Kang Chen, Meng Wang, Ronghua Guo, Yixi Zhang, Ping Li, Ran Yan, Shun Li, Tingting Li & Yiyao Liu

  2. TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, People’s Republic of China

    Ran Yan, Fengming You & Yiyao Liu

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  1. Xiang Qin
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Qin, X., Chen, K., Wang, M. et al. Nesprin-1/2 facilitates breast cancer cell pore migration via nucleus deformation. Eur. Phys. J. Spec. Top. 232, 2739–2749 (2023). https://doi.org/10.1140/epjs/s11734-023-00930-5

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