Abstract
The molecular requirements and morphology of migrating cells can vary depending on matrix geometry; therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. We present a model of cell motility that encompasses actin-polymerization-based protrusions, actomyosin contractility, variable actin–plasma membrane linkage leading to membrane blebbing, cell–extracellular-matrix adhesion and varying extracellular matrix geometries. This is used to explore the theoretical requirements for rapid migration in different matrix geometries. Confined matrix geometries cause profound shifts in the relationship of adhesion and contractility to cell velocity; indeed, cell–matrix adhesion is dispensable for migration in discontinuous confined environments. The model is challenged to predict the effect of different combinations of kinase inhibitors and integrin depletion in vivo, and in confined matrices based on in vitro two-dimensional measurements. Intravital imaging is used to verify bleb-driven migration at tumour margins, and the predicted response to single and combinatorial manipulations.
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Acknowledgements
We would like to thank R. Chaleil for his support and maintenance of the high-performance computing system, A. Weston for electron microscopy, and numerous colleagues for advice and constructive critiques.
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M.T., P.A.B. and E.S. designed the study; M.T. and A.L.T. implemented the computer algorithms; E.S. and S.H. designed and constructed the cell-based assays and in vivo experiments; R.P.J. carried out image analysis and quantification; M.T., A.L.T., P.A.B. and E.S. analysed and discussed the results; all authors contributed to the writing of the manuscript.
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Model output demonstrating the spreading of a serum-starved cell on a non-confined surface, followed by serum stimulation, rounding up and blebbing (related to Fig. 2c).
Serum-starved cell spreading on a continuous non-confined surface. Cell initiated with contractility = 0.8, and serum-stimulated = 1.6 contractility at 400 s. Cell membrane is represented in grey, actin cortex in green and myosin in red. Scale bar, 5 μm. (AVI 7867 kb)
Phase contrast movie and fluorescence movie of MLC–GFP of a serum-starved cell on a collagen matrix, followed by serum stimulation at 180 s (related to Fig. 2d).
(i) Phase contrast movie of a serum-starved cell on a collagen matrix. 1% FCS is added at frame 45. Frames are 4 s apart. (ii) Fluorescence movie of MLC–GFP of a serum-starved cell on a collagen matrix. 1% FCS is added at frame 45. Frames are 4 s apart. (AVI 12195 kb)
Computational simulations of cell migration on a 2D surface (related to Fig. 3c).
(i) Simulation of a cell moving on a continuous non-confined surface. Cell contractility = 1.0; adhesion = 3.0; rearward asymmetries in contractility and cortex–membrane linkage are 30% and 20%, respectively. Cell membrane is represented in grey, actin cortex in green and myosin in red. The colour intensities, scaled to protein concentrations, are overlaid (for example, generating the colour orange for myosin-high actin regions). Arrows indicate the forces exerted on the matrix (red, high force; green, intermediate; and blue, low). The logarithmic scale for the forces exerted is given on the video, in the range 1×10−3 pN to 1×103 pN. (ii) A zoomed-in view of the cell protrusion is shown. (iii) A zoomed-in view of the cell rear is shown. Scale bar, 5 μm. (AVI 12423 kb)
Computational simulations of cell migration in a confined continuous environment (related to Fig. 3c).
The confinement size is 10 μm. Cell contractility = 1.0; adhesion = 3.0; rearward asymmetries in contractility and cortex–membrane linkage are 30% and 20%, respectively. Colours are as in Supplementary Video S3. Scale bar, 5 μm. The cortex inside the actin-polymerization-based protrusions decay in time, and the density of these structures are colour coded in the movie, leading to greyish colours on these linkers close to the complete disassembly (which should not be confused with the colour coding of the cell membrane which lies outside the actin cortex). (AVI 16699 kb)
Computational simulations of cell migration in a confined continuous environment (related to Fig. 3c).
The confinement size is 10 μm. Cell contractility = 1.5; adhesion = 3.0; rearward asymmetries in contractility and cortex–membrane linkage are 30% and 20%, respectively. Colours are as in Supplementary Video S3. Scale bar, 5 μm. The cortex at plasma membrane bleb necks decay in time, and the density of these structures are colour coded in the movie, leading to greyish colours on these linkers close to the complete disassembly (which should not be confused with the colour coding of the cell membrane which lies outside the actin cortex). (AVI 9036 kb)
Computational simulations of cell migration in a confined discontinuous environment (related to Fig. 3c).
Vertical confinement is 10 μm and lateral gaps are 4.3 μm. Cell contractility = 1.5; adhesion = 0; rearward asymmetries in contractility and cortex–membrane linkage are 30% and 20%, respectively. Colours are as in Supplementary Video S3. The cortex at plasma membrane bleb necks decay in time, and the density of these structures are colour coded in the movie, leading to greyish colours on these linkers close to the complete disassembly (which should not be confused with the colour coding of the cell membrane which lies outside the actin cortex). (AVI 2089 kb)
A375M2 cell in the in vivo mimetic environment (related to Fig. 5b).
Cell has 50% increased contractility at the cell rear and 40% reduced cortex membrane linkers at the front. Cell moves using blebs to propel the plasma membrane forward. Cell membrane is represented in grey, actin cortex in green and myosin in red. The cortex at plasma membrane bleb necks decay in time, and the density of these structures are colour coded in the movie, leading to greyish colours on these linkers close to the complete disassembly (which should not be confused with the colour coding of the cell membrane, which lies outside the actin cortex). (AVI 22607 kb)
Moving A375M2 cell in vivo (related to Fig. 5biii).
Intravital imaging showing A375M2 cell moving at the tumour margin: green shows LifeAct and red shows histone H2B. Movie spans 24 min. (AVI 934 kb)
Moving A375M2 cells in vivo (related to Supplementary Fig. S5).
(A) Intravital imaging showing A375M2 cell moving at the tumour margin: green shows LifeAct and red shows histone H2B. Movie spans 37 min. (AVI 2349 kb)
MDA-MB-231 cell in the in vivo mimetic environment (related to Fig. 5a).
Cell has 50% increased contractility at the cell rear and 40% reduced cortex membrane linkers at the front. Cell moves using blebs to propel the plasma membrane forward. Cell membrane is represented in grey, actin cortex in green and myosin in red. Scale bar, 5 μm. (AVI 19008 kb)
Moving MDA-MB-231 cell in vivo (related to Fig. 5d).
Intravital imaging showing A375M2 cell moving at the tumour margin: green shows LifeAct and magenta shows collagen second harmonic signal. Movie spans 10 min. (AVI 1606 kb)
Blebbing migration in a primary human cancer biopsy (related to Fig. 5e).
Timelapse imaging shows migration of cell from a primary human oral squamous cell carcinoma moving between two planar collagen-rich matrices. Movie spans 120 min. (AVI 534 kb)
β1 Integrin depleted A375M2 cell in vivo (related to Fig. 6e).
Intravital imaging showing integrin-β1-depleted A375M2 cell moving: green shows LifeAct-GFP. Movie spans 30 min. Details of blebbing events are marked in Fig. 6e. (AVI 100 kb)
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Tozluoğlu, M., Tournier, A., Jenkins, R. et al. Matrix geometry determines optimal cancer cell migration strategy and modulates response to interventions. Nat Cell Biol 15, 751–762 (2013). https://doi.org/10.1038/ncb2775
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DOI: https://doi.org/10.1038/ncb2775
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