Investigating the Mechanobiology of Cancer Cell–ECM Interaction Through Collagen-Based 3D Scaffolds

Deregulated dynamics of the extracellular matrix (ECM) are one of the hallmarks of cancer. Studies on tumor mechanobiology are thus expected to provide an insight into the disease pathogenesis as well as potentially useful biomarkers. Type I collagen is among the major determinants of breast ECM structural and tensile properties, and collagen modifications during tumor evolution drive a number of disease-related processes favoring cancer progression and invasion. We investigated the use of 3D collagen-based scaffolds to identify the modifications induced by cancer cells on the mechanical and structural properties of the matrix, comparing cell lines from two breast tumor subtypes with different clinical aggressiveness. Orthotopic implantation was used to investigate the collagen content and architecture of in vivo breast tumors generated by the two cell lines. MDA-MB-231, which belongs to the aggressive basal-like subtype, increased scaffold stiffness and overexpressed the matrix-modifying enzyme, lysyl oxidase (LOX), whereas luminal A MCF-7 cells did not significantly alter the mechanical characteristics of extracellular collagen. This replicates the behavior of in vivo tumors generated by MDA-MB-231, characterized by a higher collagen content and higher LOX levels than MCF-7. When LOX activity was blocked, the ability of MDA-MB-231 to alter scaffold stiffness was impaired. Our model could constitute a relevant in vitro tool to reproduce and investigate the biomechanical interplay subsisting between cancer cells and the surrounding ECM and its impact on tumor phenotype and behavior.