Skip to main content

Research Repository

Advanced Search

Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition

Smith, Stuart J.; Wilson, Martin; Ward, Jennifer H.; Rahman, Cheryl V.; Peet, Andrew C.; Macarthur, Donald C.; Rose, Felicity R.A.J.; Grundy, Richard G.; Rahman, Ruman

Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition Thumbnail


Clinical Associate Professor

Martin Wilson

Jennifer H. Ward

Cheryl V. Rahman

Andrew C. Peet

Donald C. Macarthur

Profile Image

Professor of Biomaterials and Tissue Engineering

Richard G. Grundy



Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS).


CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat.


Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches.


Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system.

Journal Article Type Article
Acceptance Date Nov 16, 2012
Publication Date Dec 18, 2012
Deposit Date Oct 19, 2016
Publicly Available Date Oct 19, 2016
Journal PloS one
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 7
Issue 12
Article Number e52335
Public URL
Publisher URL


You might also like

Downloadable Citations