Realizations of highly heterogeneous collagen networks via stochastic reconstruction for micromechanical analysis of tumor cell invasion

Hanqing Nan, Long Liang, Guo Chen, Liyu Liu, Ruchuan Liu, Yang Jiao

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Three-dimensional (3D) collective cell migration in a collagen-based extracellular matrix (ECM) is among one of the most significant topics in developmental biology, cancer progression, tissue regeneration, and immune response. Recent studies have suggested that collagen-fiber mediated force transmission in cellularized ECM plays an important role in stress homeostasis and regulation of collective cellular behaviors. Motivated by the recent in vitro observation that oriented collagen can significantly enhance the penetration of migrating breast cancer cells into dense Matrigel which mimics the intravasation process in vivo [Han Proc. Natl. Acad. Sci. USA 113, 11208 (2016)PNASA60027-842410.1073/pnas.1610347113], we devise a procedure for generating realizations of highly heterogeneous 3D collagen networks with prescribed microstructural statistics via stochastic optimization. Specifically, a collagen network is represented via the graph (node-bond) model and the microstructural statistics considered include the cross-link (node) density, valence distribution, fiber (bond) length distribution, as well as fiber orientation distribution. An optimization problem is formulated in which the objective function is defined as the squared difference between a set of target microstructural statistics and the corresponding statistics for the simulated network. Simulated annealing is employed to solve the optimization problem by evolving an initial network via random perturbations to generate realizations of homogeneous networks with randomly oriented fibers, homogeneous networks with aligned fibers, heterogeneous networks with a continuous variation of fiber orientation along a prescribed direction, as well as a binary system containing a collagen region with aligned fibers and a dense Matrigel region with randomly oriented fibers. The generation and propagation of active forces in the simulated networks due to polarized contraction of an embedded ellipsoidal cell and a small group of cells are analyzed by considering a nonlinear fiber model incorporating strain hardening upon large stretching and buckling upon compression. Our analysis shows that oriented fibers can significantly enhance long-range force transmission in the network. Moreover, in the oriented-collagen-Matrigel system, the forces generated by a polarized cell in collagen can penetrate deeply into the Matrigel region. The stressed Matrigel fibers could provide contact guidance for the migrating cell cells, and thus enhance their penetration into Matrigel. This suggests a possible mechanism for the observed enhanced intravasation by oriented collagen.

Original languageEnglish (US)
Article number033311
JournalPhysical Review E
Issue number3
StatePublished - Mar 21 2018

ASJC Scopus subject areas

  • Statistical and Nonlinear Physics
  • Statistics and Probability
  • Condensed Matter Physics


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