Correction: Collective forces of tumor spheroids in three-dimensional biopolymer networks

Mark, Christoph; Grundy, Thomas J; Strissel, Pamela L.; Böhringer, David; Grummel, Nadine; Gerum, Richard; Steinwachs, Julian; Hack, Carolin C.; Beckmann, Matthias W.; Eckstein, Markus; Strick, Reiner; O’Neill, Geraldine M.; Fabry, Ben

doi:10.7554/elife.59538

Cited by 6 publications

(9 citation statements)

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“…Instead, by imaging the collagen substrate and spheroid immediately after embedding, we obtained a ‘natural’ reference state before sufficient time had elapsed for cells to appreciably deform the collagen substrate. (This method is corroborated by a similar ‘natural’ reference state approach that was recently applied to TFM for embedded spheroid systems using far-field deformation measurements 35 .) As a result, we were able to continuously monitor the evolving substrate deformations as long as our image registration algorithm could be trusted.…”

Section: Discussionmentioning

confidence: 58%

“…These data revealed contraction of the collagen toward the spheroid body, with the strength of contraction varying as a function of position. Regions of collagen with stronger displacements likely indicate areas where the spheroid may be exerting stronger contractile forces, although a quantitative reconstruction of CTFs would be required to verify this hypothesis 35 . However, even in the absence of CTF reconstructions, this deformation data alone can provide valuable information for learning about cell/spheroid behavior 31 , 36 .…”

Section: Resultsmentioning

confidence: 99%

“…This makes collagen supremely difficult to characterize and model to the degree necessary for numerical CTF-reconstruction schemes. Researchers have begun to make forays into addressing this challenge 26 , 35 . For example, Han et al .…”

Section: Discussionmentioning

confidence: 99%

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Computational 4D-OCM for label-free imaging of collective cell invasion and force-mediated deformations in collagen

Mulligan

Leartprapun

et al. 2021

Sci Rep

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Traction force microscopy (TFM) is an important family of techniques used to measure and study the role of cellular traction forces (CTFs) associated with many biological processes. However, current standard TFM methods rely on imaging techniques that do not provide the experimental capabilities necessary to study CTFs within 3D collective and dynamic systems embedded within optically scattering media. Traction force optical coherence microscopy (TF-OCM) was developed to address these needs, but has only been demonstrated for the study of isolated cells embedded within optically clear media. Here, we present computational 4D-OCM methods that enable the study of dynamic invasion behavior of large tumor spheroids embedded in collagen. Our multi-day, time-lapse imaging data provided detailed visualizations of evolving spheroid morphology, collagen degradation, and collagen deformation, all using label-free scattering contrast. These capabilities, which provided insights into how stromal cells affect cancer progression, significantly expand access to critical data about biophysical interactions of cells with their environment, and lay the foundation for future efforts toward volumetric, time-lapse reconstructions of collective CTFs with TF-OCM.

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Section: Discussionmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

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Computational 4D-OCM for label-free imaging of collective cell invasion and force-mediated deformations in collagen

Mulligan

Leartprapun

et al. 2021

Sci Rep

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“…Understanding how CAFs influence the architecture of collagen is key to improving our understanding of cancer cell invasion through a dense collagenous stroma as observed in breast, lung and pancreatic cancers. At macroscopic scales, this can be studied with gel-contraction assays (57-59) and bead tracking (60)(61)(62)(63), whereby the mechanical deformation of the collagen matrix is monitored without having to explicitly consider the underlying remodelling of the collagen network. More detailed understanding of the process, based on local influence of individual cells on the matrix and the biochemical interactions involved can be obtained using atomicforce and confocal microscopy at the scale of the cells (64).…”

Section: Introductionmentioning

confidence: 99%

“…From a methodological point of view, the application of the grey-tone model to analyze the structure of the 2 mg/mL and 3 mg/mL gels in both CRM and CFM modes, validated the overall image analysis approach and enabled us to apply it to the dynamic model of CAF spheroid invasion (Figures 9, 10). Matrix remodelling has been widely documented in earlier works (63,(101)(102)(103)(104). Contractility of collagen-embedded cells generates strains on the collagen fibres, leading to their local densification (19,105) and reorganization (102, 103, 106).…”

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confidence: 96%

Remodelling of the fibre-aggregate structure of collagen gels by cancer-associated fibroblasts: A time-resolved grey-tone image analysis based on stochastic modelling

et al. 2023

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IntroductionSolid tumors consist of tumor cells associated with stromal and immune cells, secreted factors and extracellular matrix (ECM), which together constitute the tumor microenvironment. Among stromal cells, activated fibroblasts, known as cancer-associated fibroblasts (CAFs) are of particular interest. CAFs secrete a plethora of ECM components including collagen and modulate the architecture of the ECM, thereby influencing cancer cell migration. The characterization of the collagen fibre network and its space and time-dependent microstructural modifications is key to investigating the interactions between cells and the ECM. Developing image analysis tools for that purpose is still a challenge because the structural complexity of the collagen network calls for specific statistical descriptors. Moreover, the low signal-to-noise ratio of imaging techniques available for time-resolved studies rules out standard methods based on image segmentation.MethodsIn this work, we develop a novel approach based on the stochastic modelling of the gel structure and on grey-tone image analysis. The method is then used to study the remodelling of a collagen matrix by migrating breast cancer-derived CAFs in a three-dimensional spheroid model of cellular invasion imaged by time-lapse confocal microscopy.ResultsThe structure of the collagen at the scale of a few microns consists in regions with high fibre density separated by depleted regions, which can be thought of as aggregates and pores. The approach developped captures this two-scale structure with a clipped Gaussian field model to describe the aggregates-and-pores large-scale structure, and a homogeneous Boolean model to describe the small-scale fibre network within the aggregates. The model parameters are identified by fitting the grey-tone histograms and correlation functions of the images. The method applies to unprocessed grey-tone images, and it can therefore be used with low magnification, noisy time-lapse reflectance images. When applied to the CAF spheroid time-resolved images, the method reveals different matrix densification mechanisms for the matrix in direct contact or far from the cells.ConclusionWe developed a novel and multidisciplinary image analysis approach to investigate the remodelling of fibrillar collagen in a 3D spheroid model of cellular invasion. The specificity of the method is that it applies to the unprocessed grey-tone images, and it can therefore be used with noisy time-lapse reflectance images of non-fluorescent collagen. When applied to the CAF spheroid time-resolved images, the method reveals different matrix densification mechanisms for the matrix in direct contact or far from the cells.

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Guided assembly of cancer ellipsoid on suspended hydrogel microfibers estimates multi-cellular traction force

et al. 2021

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Three-dimensional (3D) multi-cellular aggregates hold important applications in tissue engineering and in vitro biological modeling. Probing the intrinsic forces generated during the aggregation process, could open up new possibilities in advancing the discovery of tissue mechanics-based biomarkers. We use individually suspended, and tethered gelatin hydrogel microfibers to guide multicellular aggregation of brain cancer cells (glioblastoma cell line, U87), forming characteristic cancer ‘ellipsoids’. Over a culture period of up to 13 days, U87 aggregates evolve from a flexible cell string with cell coverage following the relaxed and curly fiber contour; to a distinct ellipsoid-on-string morphology, where the fiber segment connecting the ellipsoid poles become taut. Fluorescence imaging revealed the fiber segment embedded within the ellipsoidal aggregate to exhibit a morphological transition analogous to filament buckling under a compressive force. By treating the multicellular aggregate as an effective elastic medium where the microfiber is embedded, we applied a filament post-buckling theory to model the fiber morphology, deducing the apparent elasticity of the cancer ellipsoid medium, as well as the collective traction force inherent in the aggregation process.

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Correction: Collective forces of tumor spheroids in three-dimensional biopolymer networks

Cited by 6 publications

References 0 publications

Computational 4D-OCM for label-free imaging of collective cell invasion and force-mediated deformations in collagen

Computational 4D-OCM for label-free imaging of collective cell invasion and force-mediated deformations in collagen

Remodelling of the fibre-aggregate structure of collagen gels by cancer-associated fibroblasts: A time-resolved grey-tone image analysis based on stochastic modelling

Guided assembly of cancer ellipsoid on suspended hydrogel microfibers estimates multi-cellular traction force

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