Development of three-dimensional collagen scaffolds with controlled architecture for cell migration studies using breast cancer cell lines

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Campbell, JJ 
Hume, RD 
Watson, CJ 
Cameron, RE 

Cancer is characterized by cell heterogeneity and the development of 3D in vitro  assays that can distinguish more invasive or migratory phenotypes could enhance diagnosis or drug discovery. 3D collagen scaffolds have been used to develop analogues of complex tissues in vitro  and are suited to routine biochemical and immunological assays. We sought to increase 3D model tractability and modulate the migration rate of seeded cells using an ice-templating technique to create either directional/anisotropic or non-directional/isotropic porous architectures within cross-linked collagen scaffolds. Anisotropic scaffolds supported the enhanced migration of an invasive breast cancer cell line MDA-MB-231 with an altered spatial distribution of proliferative cells in contrast to invasive MDA-MB-468 and non-invasive MCF-7 cells lines. In addition, MDA-MB-468 showed increased migration upon epithelial-to-mesenchymal transition (EMT) in anisotropic scaffolds. The provision of controlled architecture in this system may act both to increase assay robustness and as a tuneable parameter to capture detection of a migrated population within a set time, with consequences for primary tumour migration analysis. The separation of invasive clones from a cancer biomass with in vitro platforms could enhance drug development and diagnosis testing by contributing assay metrics including migration rate, as well as modelling cell-cell and cell-matrix interaction in a system compatible with routine histopathological testing.

breast cancer, three dimensional migration, collagen 1, ice-templating technique, scaffold architecture, invasion
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National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/K001655/1)
Medical Research Council (MR/K011014/1)
Cancer Research Institute (CRI) (unknown)
Biotechnology and Biological Sciences Research Council (BB/H006206/1)
European Research Council (320598)
The authors gratefully acknowledge the financial support of the ERC Advanced Grant 320598 3D-E and the Newton Trust. A.H. held a Daphne Jackson Fellowship funded by the University of Cambridge for part of the work. R.D.H. is funded through a NC3Rs studentship.