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Cell swelling, softening and invasion in a three-dimensional breast cancer model


Control of the structure and function of three-dimensional multicellular tissues depends critically on the spatial and temporal coordination of cellular physical properties, yet the organizational principles that govern these events and their disruption in disease remain poorly understood. Using a multicellular mammary cancer organoid model, we map here the spatial and temporal evolution of positions, motions and physical characteristics of individual cells in three dimensions. Compared with cells in the organoid core, cells at the organoid periphery and the invasive front are found to be systematically softer, larger and more dynamic. These mechanical changes are shown to arise from supracellular fluid flow through gap junctions, the suppression of which delays the transition to an invasive phenotype. These findings highlight the role of spatiotemporal coordination of cellular physical properties in tissue organization and disease progression.

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Fig. 1: Evolution of heterogeneity and subpopulations of cell stiffness in the growing cancer organoid.
Fig. 2: Different cell subpopulations in a cancer organoid show distinct dynamic behaviours.
Fig. 3: Temporal and spatial evolution of cell volume during the growth of cancer organoids.
Fig. 4: Characterization of cell volume heterogeneity in patient samples.
Fig. 5: Stiffening the soft cell subpopulation inhibits the invasion of the tumour cells.

Data availability

Data supporting the findings of this study are available within the article and the Supplementary Information and Source Data and from the corresponding author on reasonable request.

Code availability

MATLAB scripts used in this work are available from the corresponding author on reasonable request.


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This work was supported by National Cancer Institute grant no. 1U01CA202123. J.J.F. is also supported by National Institute of Health grant nos. R01HL148152 and PO1HL120839. M.G. also acknowledges support from the Department of Mechanical Engineering at the Massachusetts Institute of Technology.

Author information




Y.L.H. and M.G. designed the experiments. M.G. supervised the project. Y.L.H., H.L., Z.G., K.L., H.K., Y.Y., Y.L., W.T. and L.T. performed the experiments. Y.L.H., A.F.P., G.X., Z.G., J.S., Y.H. and S.K.G. developed MATLAB scripts for image processing and data analysis. Y.L.H., A.F.P., J.J.F. and M.G. wrote the manuscript. All authors edited and approved the manuscript.

Corresponding author

Correspondence to Ming Guo.

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Supplementary information

Supplementary Information

Supplementary Table 1, Figs. 1–14 and refs. 1 and 2.

Reporting Summary

Supplementary Video 1

Middle-stage tumour microdynamics before transitioning to an invasive behaviour.

Supplementary Video 2

Later-stage tumour microdynamics after transitioning to an invasive behaviour.

Supplementary Video 3

Confocal images of malignant acini from grade-2 ER+ human invasive-ductal-carcinoma samples.

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Han, Y.L., Pegoraro, A.F., Li, H. et al. Cell swelling, softening and invasion in a three-dimensional breast cancer model. Nat. Phys. 16, 101–108 (2020).

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