The effect of fibrillar matrix architecture on tumor cell invasion of physically challenging environments.
Local invasion by and dissemination of cancer cells from a primary tumor are key initial steps of metastasis, the most lethal aspect of cancer. To study these processes in vitro, the invasion of cells from multicellular breast cancer aggregates embedded in three-dimensional (3D) extracellular matrix culture systems was studied. This work showed that in 3D fibrillar environments composed of collagen I, pore size--not the viscoelastic properties of the matrix--was the biophysical characteristic controlling breast cancer cell invasion efficiency. Furthermore, it was shown that fibrillar matrix architecture is a crucial factor that allows for efficient 3D invasion. In a 3D non-fibrillar environment composed of basement membrane extract (BME), invasion efficiency was greatly diminished, the mesenchymal individual mode of 3D invasion was abolished, and establishment of cell polarity and protrusions was compromised. These effects were seen even though the BME matrix has invasion permissive viscoelasticity and suitable adhesion ligands. The altered and limited invasive behavior observed in BME was rescued through introduction of fibrillar collagen into the non-fibrillar matrix. The biophysical cues of fibrillar collagen facilitated efficient invasion of sterically disadvantageous environments through assisting cell polarization and formation of stable cell protrusions. Finally, we suggest the composite matrices employed in this study consisting of fibrillar collagen I and BME in either a liquid-like or gelled state are suitable for a wide range of 3D cell studies, as these matrices combine fibrillar features that require cells to deploy integrin-dependent mechanotransduction machinery and a tunable non-fibrillar component that may require cells to adopt alternative migratory modes.
Department of Chemistry, Columbia University, New York, NY 10027, USA.
Asja
A
Guzman
Department of Chemistry, Columbia University, New York, NY 10027, USA.
Michelle J
MJ
Ziperstein
Department of Chemistry, Columbia University, New York, NY 10027, USA. Electronic address: kaufman@chem.columbia.edu.
Laura J
LJ
Kaufman
D001485:Basement Membrane / Q000737:chemistry; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D024042:Collagen Type I / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D024022:Fibrillar Collagens / Q000737:chemistry*; D006801:Humans; D040542:Mechanotransduction, Cellular; D016062:Porosity
D024042:Collagen Type I; D024022:Fibrillar Collagens
3D; Breast cancer; Cell invasion; Collagen; Extracellular matrix