Mammary fibroblasts remodel fibrillar collagen microstructure in a biomimetic nanocomposite hydrogel

Abstract

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.

Hydrogels to engineer tumor microenvironmentsin vitro

“…Interestingly, the remodeled collagen matrix was thicker and aligned perpendicular to spheroids, and facilitated the invasion of cancer cells. 302 Collectively, these studies underscore the importance of the hydrogel…”

Proteinaceous Hydrogels for Bioengineering Advanced 3D Tumor Models

“…[ 175 ] In an elegant approach, nanosized polyhedral oligomeric silsesquioxanes were introduced in Col I/alginate hydrogels to study the effect of matrix remodeling in cell migration ( Figure a–f). [ 176 ] The combination of these materials enabled the generation of different fibrillar collagen structures, while assuring constant stiffness and porosity. Human mammary fibroblasts (HMFs) and MDA‐MB‐231 mamospheres were cultured in such hydrogels, which stimulated fibroblasts to remodel the collagen microstructure, facilitating cancer cells invasion.…”

“…Human mammary fibroblasts (HMFs) and MDA‐MB‐231 mamospheres were cultured in such hydrogels, which stimulated fibroblasts to remodel the collagen microstructure, facilitating cancer cells invasion. [ 176 ] Col I/alginate hydrogel platforms were also explored to evaluate ECM remodeling influence in the cross‐talk between CAFs and cancer cells. For this purpose, researchers synthetized hydrogels with stiffness ranging from 108 to 898 Pa, and recapitulated the breast TME using CAFs and metastatic breast cancer cells (MDA‐MB‐231).…”

“…Reproduced with permission. [ 176 ] Copyright 2019, Elsevier. g) Fabrication of organoid spheroidal constructs made of collagen I methacrylate and thiolated‐HA by 3D‐printing technology in a gelatin bath compatible with HTS.…”

Biomass/polyhedral oligomeric silsesquioxane nanocomposites: Advances in preparation strategies and performances

“…By incorporating trisilanolisobutyl-POSS (TSB-POSS) and PEGylated-POSS (PEG-POSS) into a collagen/alginate matrix, Chun Liu [82] prepared biomimetic nanocomposite hydrogels, that showing different fibrillary collagen microstructures without changing matrix stiffness, density, and porosity. Compression modulus of the prepared hydrogel increased by 75 and 60% with 1% TSB-POSS or PEG-POSS, respectively.…”