title: The phenotype of cancer cell invasion controlled by fibril diameter and pore size of 3D collagen networks.
abstract: The behavior of cancer cells is strongly influenced by the properties of extracellular microenvironments, including topology, mechanics and composition. As topological and mechanical properties of the extracellular matrix are hard to access and control for in-depth studies of underlying mechanisms in vivo, defined biomimetic in vitro models are needed. Herein we show, how pore size and fibril diameter of collagen I networks distinctively regulate cancer cell morphology and invasion. Three-dimensional collagen I matrices with a tight control of pore size, fibril diameter and stiffness were reconstituted by adjustment of concentration and pH value during matrix reconstitution. At first, a detailed analysis of topology and mechanics of matrices using confocal laser scanning microscopy, image analysis tools and force spectroscopy indicate pore size and not fibril diameter as the major determinant of matrix elasticity. Secondly, by using two different breast cancer cell lines (MDA-MB-231 and MCF-7), we demonstrate collagen fibril diameter--and not pore size--to primarily regulate cell morphology, cluster formation and invasion. Invasiveness increased and clustering decreased with increasing fibril diameter for both, the highly invasive MDA-MB-231 cells with mesenchymal migratory phenotype and the MCF-7 cells with amoeboid migratory phenotype. As this behavior was independent of overall pore size, matrix elasticity is shown to be not the major determinant of the cell characteristics. Our work emphasizes the complex relationship between structural-mechanical properties of the extracellular matrix and invasive behavior of cancer cells. It suggests a correlation of migratory and invasive phenotype of cancer cells in dependence on topological and mechanical features of the length scale of single fibrils and not on coarse-grained network properties.
authors.affiliation: Biophysical Chemistry Group, Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Leipzig 04103, Germany.
authors.forename: Jiranuwat
authors.initials: J
authors.lastname: Sapudom
authors.affiliation: Biophysical Chemistry Group, Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Leipzig 04103, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rubner
authors.affiliation: Biophysical Chemistry Group, Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Leipzig 04103, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Martin
authors.affiliation: Biological Physics Division, Institute for Experimental Physics I, Faculty of Physics and Earth Science, Universität Leipzig, 04103 Leipzig, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Kurth
authors.affiliation: Biological Physics Division, Institute for Experimental Physics I, Faculty of Physics and Earth Science, Universität Leipzig, 04103 Leipzig, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Riedel
authors.affiliation: Biological Physics Division, Institute for Experimental Physics I, Faculty of Physics and Earth Science, Universität Leipzig, 04103 Leipzig, Germany.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: Mierke
authors.affiliation: Biophysical Chemistry Group, Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Leipzig 04103, Germany. Electronic address: tilo.pompe@uni-leipzig.de.
authors.forename: Tilo
authors.initials: T
authors.lastname: Pompe
mesh_terms: D032701:Biomimetics; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement; D024042:Collagen Type I / Q000737:chemistry*; D003102:Colloids / Q000737:chemistry; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D013314:Stress, Mechanical
chemical_list: D024042:Collagen Type I; D003102:Colloids
keywords: Cell morphology; Collagen; ECM (extracellular matrix); Invasion; Mechanical properties; Microstructure