Architecture and microstructure of
type I collagen fibers constitute central regulators of
tumor invasion with aligned fibers providing a route for migration of stromal and
cancer cells. Several different aspects of
fibrillar collagen, such as stiffness, density, thickness, and pore size, may regulate migration of
cancer cells, but determining effects of any one parameter requires clear decoupling of physical properties of
collagen networks. The objective of this work is to develop and apply an in vitro three-dimensional (3D)
tumor-extra cellular matrix (ECM) model with tunable physical parameters to define how stromal fibroblasts modulate
collagen microstructure to control migration of
breast cancer cells. We incorporated two different types of polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a
collagen/
alginate matrix to induce different mechanisms of gelling. The resultant biomimetic,
nanocomposite hydrogels show different
collagen fibrillar microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. Spheroids of human mammary fibroblasts embedded in these 3D matrices remodel the
collagen network to varying extents based on differences in underlying matrix microstructures. The remodeled
collagen matrix shows oriented, thicker fibrillar tracks, facilitating invasion of
tumor cells. By decoupling effects of matrix stiffness and architecture, our
nanocomposite hydrogels serve as robust platforms to investigate how biophysical properties of
tumor environments control key processes regulating
tumor progression in
breast cancer and other
malignancies. STATEMENT OF SIGNIFICANCE: Our manuscript demonstrates a new type of
nanocomposite hydrogel with two different gelling mechanisms, produced by incorporating two types of polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a
collagen/
alginate matrix. The resultant biomimetic
hydrogels show different
fibrillar collagen microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. These
gels allow us to uncouple effects of matrix stiffness versus architecture on migration and invasion of
breast cancer cells and stromal fibroblasts. Upon embedding spheroids of human mammary fibroblasts (HMFs) and dissociated 231
breast cancer cells, we showed that HMFs remodeled the
collagen network to differing extents dependent on starting matrix microstructures in each
hydrogel. The remodeled
collagen matrix showed aligned
collagen fibers perpendicular to the surface of a spheroid with migrating HMFs following these fibers as occurs in
tumors in vivo. To our knowledge, this is the first study showing significant different
fibrillar collagen microstructures with constant
collagen density and gel stiffness. This study establishes a new type of nanocomposite 3D
hydrogels for studies of biophysical and cellular interactions in engineered
tumor environments.