Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy

Hilary A. Kenny (), Madhu Lal-Nag, Erin A. White, Min Shen, Chun-Yi Chiang, Anirban K. Mitra, Yilin Zhang, Marion Curtis, Elizabeth M. Schryver, Sam Bettis, Ajit Jadhav, Matthew B. Boxer, Zhuyin Li, Marc Ferrer and Ernst Lengyel ()
Additional contact information
Hilary A. Kenny: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Madhu Lal-Nag: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Erin A. White: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Min Shen: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Chun-Yi Chiang: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Anirban K. Mitra: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Yilin Zhang: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Marion Curtis: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Elizabeth M. Schryver: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Sam Bettis: Institute of Genomics and Systems Biology, University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA
Ajit Jadhav: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Matthew B. Boxer: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Zhuyin Li: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Marc Ferrer: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Building B, Rockville, Maryland 20850, USA
Ernst Lengyel: University of Chicago, 5841 South Maryland Avenue, MC2050, Chicago, Illinois 60637, USA

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial cells and extracellular matrix can be adapted into a reliable 384- and 1,536-multi-well HTS assay that reproduces the human ovarian cancer (OvCa) metastatic microenvironment. We validate the identified inhibitors in secondary in vitro and in vivo biological assays using three OvCa cell lines: HeyA8, SKOV3ip1 and Tyk-nu. The active compounds directly inhibit at least two of the three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that a complex three-dimensional culture of the tumour microenvironment can be adapted for quantitative HTS and may improve the disease relevance of assays used for drug screening.

Date: 2015
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DOI: 10.1038/ncomms7220

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