Benchmarking to the Gold Standard: Hyaluronan‐Oxime Hydrogels Recapitulate Xenograft Models with In Vitro Breast Cancer Spheroid Culture

• Published in: Advanced materials (Weinheim) 2019-09, Vol.31 (36), p.e1901166-n/a
• Main Authors: Baker, Alexander E. G., Bahlmann, Laura C., Tam, Roger Y., Liu, Jeffrey C., Ganesh, Ahil N., Mitrousis, Nikolaos, Marcellus, Richard, Spears, Melanie, Bartlett, John M. S., Cescon, David W., Bader, Gary D., Shoichet, Molly S.
• Format: Article
• Language: English
• Subjects: 3D cell culture; Animals; Benchmarking; Breast cancer; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic; Crosslinking; Culture; drug screening; Gelation; Gene expression; Humans; Hyaluronic acid; Hyaluronic Acid - chemistry; Hydrogels; Hydrogels - chemistry; Hydrogels - pharmacology; Inhibitors; Materials science; Mechanical properties; Mice; Oximes - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Three dimensional models; Xenotransplantation
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.201901166

Many 3D in vitro models induce breast cancer spheroid formation; however, this alone does not recapitulate the complex in vivo phenotype. To effectively screen therapeutics, it is urgently needed to validate in vitro cancer spheroid models against the gold standard of xenografts. A new oxime‐crosslinked hyaluronan (HA) hydrogel is designed, manipulating gelation rate and mechanical properties to grow breast cancer spheroids in 3D. This HA‐oxime breast cancer model maintains the gene expression profile most similar to that of tumor xenografts based on a pan‐cancer gene expression profile (comprising 730 genes) of three different human breast cancer subtypes compared to Matrigel or conventional 2D culture. Differences in gene expression between breast cancer cultures in HA‐oxime versus Matrigel or 2D are confirmed for 12 canonical pathways by gene set variation analysis. Importantly, drug response is dependent on the culture method. Breast cancer cells respond better to the Rac inhibitor (EHT‐1864) and the PI3K inhibitor (AZD6482) when cultured in HA‐oxime versus Matrigel. This study demonstrates the superiority of an HA‐based hydrogel as a platform for in vitro breast cancer culture of both primary, patient‐derived cells and cell lines, and provides a hydrogel culture model that closely matches that in vivo. The first oxime‐crosslinked hyaluronan‐based hydrogel is synthesized as a platform for in vitro 3D culture of both primary, patient‐derived breast cancer cells and cell lines. The superiority of this system over other common strategies relative to in vivo models is demonstrated, thereby providing an in vitro biomimetic system for use in drug screening and personalized medicine.