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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

Authors

STUART SMITH stuart.smith@nottingham.ac.uk
Clinical Associate Professor

Martin Wilson

Jennifer H. Ward

Cheryl V. Rahman

Andrew C. Peet

Donald C. Macarthur

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FELICITY ROSE FELICITY.ROSE@NOTTINGHAM.AC.UK
Professor of Biomaterials and Tissue Engineering

Richard G. Grundy



Abstract

INTRODUCTION

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).

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Citation

Smith, S. J., Wilson, M., Ward, J. H., Rahman, C. V., Peet, A. C., Macarthur, D. C., …Rahman, R. (2012). Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition. PLoS ONE, 7(12), https://doi.org/10.1371/journal.pone.0052335

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
DOI https://doi.org/10.1371/journal.pone.0052335
Public URL http://eprints.nottingham.ac.uk/id/eprint/37648
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052335
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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