TY - JOUR
T1 - Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion
AU - Ahmadzadeh, Hossein
AU - Webster, Marie R.
AU - Behera, Reeti
AU - Valencia, Angela M.Jimenez
AU - Wirtz, Denis
AU - Weeraratna, Ashani T.
AU - Shenoy, Vivek B.
N1 - Funding Information:
We thank Dr. James Hayden for expert assistance with image analysis. This work is supported by National Cancer Institute Grants U01CA202177 and U54CA193417 (to V.B.S.), NIH Grant R01EB017753 (to V.B.S.), and National Science Foundation Grant CMMI-1548571 (to V.B.S.). M.R.W. is supported by Grant K99 CA208012-01. Core facilities at theWistar Institute are supported by P30 CA010815. A.T.W. and R.B. are supported by Grant R01CA174746. D.W. is supported by National Cancer Institute Grant U54CA210173. Image analysis is supported by Grant P30CA010815.
PY - 2017/2/28
Y1 - 2017/2/28
N2 - Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy-based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca2+ and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongatedmorphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion.
AB - Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy-based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca2+ and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongatedmorphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion.
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U2 - 10.1073/pnas.1617037114
DO - 10.1073/pnas.1617037114
M3 - Article
C2 - 28196892
AN - SCOPUS:85014332812
SN - 0027-8424
VL - 114
SP - E1617-E1626
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -