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Abstract Embedding a collective of tumor cells, i.e. a tumor spheroid, in a fibrous environment, such as a collagen network, provides an essentialin vitroplatform to investigate the biophysical mechanisms of tumor invasion. To predict new mechanisms, we develop a three-dimensional computational model of an embedded spheroid using a vertex model, with cells represented as deformable polyhedrons, mechanically coupled to a fiber network via active linker springs. As the linker springs actively contract, the fiber network remodels. As we tune the rheology of the spheroid and the fiber network stiffness, we find that both factors affect the remodeling of the fiber network with fluid-like spheroids densifying and radially realigning the fiber network more on average than solid-like spheroids but only for a range of intermediate fiber network stiffnesses. Our predictions are supported by experimental studies comparing non-tumorigenic MCF10A spheroids and malignant MDA-MB-231 spheroids embedded in collagen networks. The spheroid rheology-dependent effects are the result of cellular motility generating spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network. This emergent feedback occurs only at intermediate fiber network stiffness since at low fiber network stiffness, the mechanical response of the coupled system is dominated by the spheroid and for high fiber network stiffness, the mechanical response is dominated by the fiber network. We are therefore able to quantify the regime of optimal spheroid-fiber network mechanical reciprocity. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strengthandspheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.
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Actively Driven Fluctuations in a Fibrin Network
Understanding force propagation through the fibrous extracellular matrix can elucidate how cells interact mechanically with their surrounding tissue. Presumably, due to elastic nonlinearities of the constituent filaments and their random connection topology, force propagation in fiber networks is quite complex, and the basic problem of force propagation in structurally heterogeneous networks remains unsolved. We report on a new technique to detect displacements through such networks in response to a localized force, using a fibrin hydrogel as an example. By studying the displacements of fibers surrounding a two-micron bead that is driven sinusoidally by optical tweezers, we develop maps of displacements in the network. Fiber movement is measured by fluorescence intensity fluctuations recorded by a laser scanning confocal microscope. We find that the Fourier magnitude of these intensity fluctuations at the drive frequency identifies fibers that are mechanically coupled to the driven bead. By examining the phase relation between the drive and the displacements, we show that the fiber displacements are, indeed, due to elastic couplings within the network. Both the Fourier magnitude and phase depend on the direction of the drive force, such that displacements typically propagate farther, but not exclusively, along the drive direction. This technique may be used to characterize the local mechanical response in 3-D tissue cultures, and to address fundamental questions about force propagation within fiber networks.
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- Award ID(s):
- 1709785
- PAR ID:
- 10220925
- Date Published:
- Journal Name:
- Frontiers in Physics
- Volume:
- 8
- ISSN:
- 2296-424X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fphy.2020.568736
