Migration in Confined 3D Environments Is Determined by a Combination of Adhesiveness, Nuclear Volume, Contractility, and Cell Stiffness.
In cancer metastasis and other physiological processes, cells migrate through the three-dimensional (3D) extracellular matrix of connective tissue and must overcome the steric hindrance posed by pores that are smaller than the cells. It is currently assumed that low cell stiffness promotes cell migration through confined spaces, but other factors such as adhesion and traction forces may be equally important. To study 3D migration under confinement in a stiff (1.77 MPa) environment, we use soft lithography to fabricate polydimethylsiloxane (PDMS) devices consisting of linear channel segments with 20 μm length, 3.7 μm height, and a decreasing width from 11.2 to 1.7 μm. To study 3D migration in a soft (550 Pa) environment, we use self-assembled collagen networks with an average pore size of 3 μm. We then measure the ability of four different cancer cell lines to migrate through these 3D matrices, and correlate the results with cell physical properties including contractility, adhesiveness, cell stiffness, and nuclear volume. Furthermore, we alter cell adhesion by coating the channel walls with different amounts of adhesion proteins, and we increase cell stiffness by overexpression of the nuclear envelope protein lamin A. Although all cell lines are able to migrate through the smallest 1.7 μm channels, we find significant differences in the migration velocity. Cell migration is impeded in cell lines with larger nuclei, lower adhesiveness, and to a lesser degree also in cells with lower contractility and higher stiffness. Our data show that the ability to overcome the steric hindrance of the matrix cannot be attributed to a single cell property but instead arises from a combination of adhesiveness, nuclear volume, contractility, and cell stiffness.
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: llautscham@biomed.uni-erlangen.de.
Lena A
LA
Lautscham
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Christoph
C
Kämmerer
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Janina R
JR
Lange
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Thorsten
T
Kolb
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Christoph
C
Mark
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Achim
A
Schilling
Laboratory for Molecular Medicine, Department of Gynecology and Obstetrics, University-Clinic Erlangen, Erlangen, Germany.
Pamela L
PL
Strissel
Laboratory for Molecular Medicine, Department of Gynecology and Obstetrics, University-Clinic Erlangen, Erlangen, Germany.
Reiner
R
Strick
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Caroline
C
Gluth
Department of Integrative Biology and Physiology, UCLA, Los Angeles, California.
Amy C
AC
Rowat
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Claus
C
Metzner
Biophysics Group, Department of Physics, University of Erlangen-Nuremberg, Erlangen, Germany.
Ben
B
Fabry
D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D053145:Cell Nucleus Size; D003094:Collagen / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D016062:Porosity
D003094:Collagen