Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis.
Muhammad H. Zaman,Linda M. Trapani,A.L. Sieminski,Drew C. MacKellar,Haiyan Gong,Roger D. Kamm,Alan Wells,Douglas A. Lauffenburger,Paul Matsudaira +8 more
TLDR
The experimental findings here represent, to the knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.Abstract:
Cell migration on 2D surfaces is governed by a balance between counteracting tractile and adhesion forces. Although biochemical factors such as adhesion receptor and ligand concentration and binding, signaling through cell adhesion complexes, and cytoskeletal structure assembly/disassembly have been studied in detail in a 2D context, the critical biochemical and biophysical parameters that affect cell migration in 3D matrices have not been quantitatively investigated. We demonstrate that, in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D. Cell migration assays in which Matrigel density, fibronectin concentration, and β1 integrin binding are systematically varied show that at a specific Matrigel density the migration speed of DU-145 human prostate carcinoma cells is a balance between tractile and adhesion forces. However, when biochemical parameters such as matrix ligand and cell integrin receptor levels are held constant, maximal cell movement shifts to matrices exhibiting lesser stiffness. This behavior contradicts current 2D models but is predicted by a recent force-based computational model of cell movement in a 3D matrix. As expected, this 3D motility through an extracellular environment of pore size much smaller than cellular dimensions does depend on proteolytic activity as broad-spectrum matrix metalloproteinase (MMP) inhibitors limit the migration of DU-145 cells and also HT-1080 fibrosarcoma cells. Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.read more
Citations
More filters
Journal ArticleDOI
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Kandice R. Levental,Hongmei Yu,Laura Kass,Johnathon N. Lakins,Mikala Egeblad,Janine T. Erler,Sheri F. T. Fong,Katalin Csiszar,Amato J. Giaccia,Wolfgang Weninger,Mitsuo Yamauchi,David L. Gasser,Valerie M. Weaver +12 more
TL;DR: Reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence, and data show how collagenCrosslinking can modulate tissue fibrosis and stiffness to force focal adhesion, growth factor signaling and breast malignancies.
Journal ArticleDOI
The third dimension bridges the gap between cell culture and live tissue
TL;DR: It is believed that 3D cultures will have a strong impact on drug screening and will also decrease the use of laboratory animals, for example, in the context of toxicity assays.
Journal ArticleDOI
Modeling Tissue Morphogenesis and Cancer in 3D
Kenneth M. Yamada,Edna Cukierman +1 more
TL;DR: Three-dimensional (3D) in vitro models provide unique perspectives on the behavior of stem cells, developing tissues and organs, and tumors and may help to accelerate translational research in cancer biology and tissue engineering.
Journal ArticleDOI
Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues
TL;DR: The focus of this Commentary will be on identifying and describing the fundamental features of 3D cell culture systems that influence cell structure, adhesion, mechanotransduction and signaling in response to soluble factors, which regulate overall cellular function in ways that depart dramatically from traditional 2D culture formats.
Journal ArticleDOI
Plasticity of cell migration: a multiscale tuning model
TL;DR: Using a multiparameter tuning model, this work describes how dimension, density, stiffness, and orientation of the extracellular matrix together with cell determinants—including cell–cell and cell–matrix adhesion, cytoskeletal polarity and stiffness, etc.—interdependently control migration mode and efficiency.
References
More filters
Journal ArticleDOI
Cell migration: integrating signals from front to back.
Anne J. Ridley,Martin A. Schwartz,Keith Burridge,Richard A. Firtel,Mark H. Ginsberg,Gary G. Borisy,J. Thomas Parsons,Alan Rick Horwitz +7 more
TL;DR: The mechanisms underlying the major steps of migration and the signaling pathways that regulate them are described, and recent advances investigating the nature of polarity in migrating cells and the pathways that establish it are outlined.
Journal ArticleDOI
Cell Migration: A Physically Integrated Molecular Process
TL;DR: The authors are grateful for financial support from the National Institutes of Health (grants GM23244 and GM53905), and to very helpful comments on the manuscript from Elliot Elson, Vlodya Gelfand, Paul Matsudaira, Julie Theriot, and Sally Zigmond.
Journal ArticleDOI
Cell locomotion and focal adhesions are regulated by substrate flexibility
Robert J. Pelham,Yu-li Wang +1 more
TL;DR: The ability of cells to survey the mechanical properties of their surrounding environment is demonstrated and the possible involvement of both protein tyrosine phosphorylation and myosin-generated cortical forces in this process is suggested.
Journal ArticleDOI
Taking Cell-Matrix Adhesions to the Third Dimension
TL;DR: These distinctive in vivo 3D-matrix adhesions differ in structure, localization, and function from classically described in vitro adhesion, and as such they may be more biologically relevant to living organisms.
Journal ArticleDOI
Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis
Katarina Wolf,Irina B. Mazo,Harry Leung,Katharina Engelke,Ulrich H. von Andrian,Elena I. Deryugina,Alex Y. Strongin,Eva B. Bröcker,Peter Friedl +8 more
TL;DR: The transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.