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

被引:61
作者
Baker, Alexander E. G. [1 ,2 ,3 ]
Bahlmann, Laura C. [1 ,3 ]
Tam, Roger Y. [1 ,2 ,3 ]
Liu, Jeffrey C. [1 ,3 ]
Ganesh, Ahil N. [1 ,2 ,3 ]
Mitrousis, Nikolaos [1 ,3 ]
Marcellus, Richard [4 ]
Spears, Melanie [4 ,5 ]
Bartlett, John M. S. [4 ]
Cescon, David W. [6 ]
Bader, Gary D. [1 ]
Shoichet, Molly S. [1 ,2 ,3 ,7 ]
机构
[1] Univ Toronto, Donnelly Ctr, 160 Coll St, Toronto, ON M5S 3E1, Canada
[2] Univ Toronto, Dept Chem Engn & Appl Chem, 200 Coll St, Toronto, ON M5S 3E5, Canada
[3] Inst Biomat & Biomed Engn, 164 Coll St, Toronto, ON M5S 3G9, Canada
[4] MaRS Ctr, Ontario Inst Canc Res, 661 Univ Ave, Toronto, ON M5G 0A3, Canada
[5] Univ Toronto, Dept Lab Med & Pathol, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada
[6] Univ Hlth Network, Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2C1, Canada
[7] Univ Toronto, Dept Chem, 80 St George St, Toronto, ON M5S 3H6, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
3D cell culture; breast cancer; drug screening; hyaluronic acid; hydrogels; CELLS; ACID; GROWTH; TISSUE; CD44; DEGRADATION; EXPRESSION; VIABILITY; RESPONSES; LAMININ;
D O I
10.1002/adma.201901166
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页数:11
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