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Mechanical transmission enables EMT cancer cells to drive epithelial cancer cell migration to guide tumor spheroid disaggregation

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Abstract

Cell phenotype heterogeneity within tumor tissue, especially which due to the emergence of epithelial-mesenchymal transition (EMT) in cancer cells, is associated with cancer invasion and metastasis. However, our understanding of the cellular mechanism(s) underlying the cooperation between EMT cell and epithelial cancer cell migration remains incomplete. Herein, heterotypic tumor spheroids containing both epithelial and EMT cancer cells were generated in vitro. We observed that EMT cells dominated the peripheral region of the self-organized heterotypic tumor spheroid. Furthermore, our results demonstrated that EMT cells could serve as leader cells to improve the collective migration efficiency of epithelial cancer cells and promote dispersion and invasion of the tumor spheroids, which was regulated by the force transition between EMT cells and epithelial cancer cells. Mechanistically, our data further suggest that force transmission is mediated by heterophilic N-cadherin/E-cadherin adhesion complexes between EMT and epithelial cancer cells. Impairment of N-cadherin/E-cadherin adhesion complex formation abrogated the ability of EMT cells to guide epithelial cancer cell migration and blocked the dispersion of tumor spheroids. Together, our data provide new insight into the mechanical interaction between epithelial and EMT cancer cells through heterophilic cadherin adhesion, which enables cooperative tumor cell migration, highlighting the role of EMT cells in tumor invasion.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (11772006, 11972002, 11902007) and China Postdoctoral Science Foundation (2019M660313).

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Authors and Affiliations

  1. Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, 100871, China

    Qing Zhang, Feng Lin, Jianyong Huang & Chunyang Xiong

  2. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China

    Feng Lin & Chunyang Xiong

  3. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, China

    Feng Lin & Chunyang Xiong

  4. Beijing Innovation Center for Engineering Science and Advanced Technology, College of Engineering, Peking University, Beijing, 100871, China

    Jianyong Huang

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Zhang, Q., Lin, F., Huang, J. et al. Mechanical transmission enables EMT cancer cells to drive epithelial cancer cell migration to guide tumor spheroid disaggregation. Sci. China Life Sci. 65, 2031–2049 (2022). https://doi.org/10.1007/s11427-021-2054-3

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