12th Annual Symposium
Physics of Cancer
Leipzig, Germany
Aug 30 - Sept 1, 2021
Contributed Talk
Cell-generated forces and matrix remodelling in 3-D disease models
David Böhringer1,2, Andreas Bauer1, Christoph Mark1, Ivana Moravec2, Richard Gerum1,3, Thomas Grundy4, Geraldine O'Neill4, Nadine Grummel1, Pamela Strissel5, Reiner Strick5, Martin Steinmann2, Jasmin Raufer6, Nico Reid6, Muhannad Alkassar6, Phuong A. Ngo7, Rocio Lopez-Posadas7, Ekkehard Goerlach2, Martin Rausch2, Ben Fabry1
1Friedrich-Alexander University Erlangen-Nürnberg, Department of Physics, Erlangen, Germany
2Novartis Institutes for BioMedical Research, Basel, Switzerland
3York University, Department of Physics and Astronomy, Toronto, Canada
4University of Sydney, The Children's Hospital at Westmead, Sydney, Australia
5Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, Department of Gynecology and Obstetrics, Erlangen, Germany
6Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, Department of Cardiac Surgery, Erlangen, Germany
7Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, Department of Medicine 1, Erlangen, Germany
Diseases such as fibrosis and cancer are often associated with disordered matrix remodeling and altered force generation. We developed and compared methods to quantify force generation of individual cells and cell assemblies (spheroids, organoids, tumoroids) in 3-D biopolymer matrices. To speed-up the computation time for 3-D force reconstruction, which can be prohibitively large in the case of cell assemblies, we introduced simplifications to exploit certain symmetrical constraints. For example, by exploiting the near-cylindrical symmetry of cardiac and skeletal muscle cells, we can simplify the force reconstruction algorithm to an algebraic expression that allows us to compute the contractility of individual muscle fibers in real-time. Similarly, by exploiting the approximately spherical symmetry in the far-field of the matrix displacements around contractile cells and cell assemblies, we measure the collective force generation of spheroids and organoids in real-time. We demonstrate that this technique can be applied to study the progression of intestinal inflammation and to explore the force-generation behavior of breast cancer-associated mesenchymal cells. Further, we demonstrate that cell-generated forces are tightly linked to matrix remodeling that we quantify by analyzing collagen fiber orientation and collagen intensity around individual cells and cell assemblies. This approach only requires imaging of the cell outline and of the fiber structure, and it can be applied without further knowledge of material properties or of the deformation-free equilibrium state. Together, these methods for quantifying force reconstruction and matrix remodeling are robust, user-friendly, and provide sufficiently high throughput to make them useful for other research questions focusing on the complex interplay between cells and their micro-environment.
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