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 Mitra, Yilin Zhang, Marion Curtis, Elizabeth M. Schryver, Sam Bettis, Ajit Jadhav, Matthew B. Boxer, Zhuyin Li, Marc Ferrer, Ernst Lengyel

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish (US)
Article number6220
JournalNature Communications
Volume6
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Ovarian Neoplasms
Tumor Microenvironment
Assays
Screening
screening
cancer
Throughput
High-Throughput Screening Assays
Tumors
drugs
Adhesion
Cells
metastasis
Neoplasm Metastasis
Preclinical Drug Evaluations
adhesion
Drug Discovery
Fibroblasts
tumors
Cell culture

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy. / Kenny, Hilary A.; Lal-Nag, Madhu; White, Erin A.; Shen, Min; Chiang, Chun Yi; Mitra, Anirban; Zhang, Yilin; Curtis, Marion; Schryver, Elizabeth M.; Bettis, Sam; Jadhav, Ajit; Boxer, Matthew B.; Li, Zhuyin; Ferrer, Marc; Lengyel, Ernst.

In: Nature Communications, Vol. 6, 6220, 2015.

Research output: Contribution to journalArticle

Kenny, HA, Lal-Nag, M, White, EA, Shen, M, Chiang, CY, Mitra, A, Zhang, Y, Curtis, M, Schryver, EM, Bettis, S, Jadhav, A, Boxer, MB, Li, Z, Ferrer, M & Lengyel, E 2015, 'Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy', Nature Communications, vol. 6, 6220. https://doi.org/10.1038/ncomms7220
Kenny, Hilary A. ; Lal-Nag, Madhu ; White, Erin A. ; Shen, Min ; Chiang, Chun Yi ; Mitra, Anirban ; Zhang, Yilin ; Curtis, Marion ; Schryver, Elizabeth M. ; Bettis, Sam ; Jadhav, Ajit ; Boxer, Matthew B. ; Li, Zhuyin ; Ferrer, Marc ; Lengyel, Ernst. / Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy. In: Nature Communications. 2015 ; Vol. 6.
@article{33d472f0790d4078b803ba7e3422c93b,
title = "Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy",
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.",
author = "Kenny, {Hilary A.} and Madhu Lal-Nag and White, {Erin A.} and Min Shen and Chiang, {Chun Yi} and Anirban Mitra and Yilin Zhang and Marion Curtis and Schryver, {Elizabeth M.} and Sam Bettis and Ajit Jadhav and Boxer, {Matthew B.} and Zhuyin Li and Marc Ferrer and Ernst Lengyel",
year = "2015",
doi = "10.1038/ncomms7220",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy

AU - Kenny, Hilary A.

AU - Lal-Nag, Madhu

AU - White, Erin A.

AU - Shen, Min

AU - Chiang, Chun Yi

AU - Mitra, Anirban

AU - Zhang, Yilin

AU - Curtis, Marion

AU - Schryver, Elizabeth M.

AU - Bettis, Sam

AU - Jadhav, Ajit

AU - Boxer, Matthew B.

AU - Li, Zhuyin

AU - Ferrer, Marc

AU - Lengyel, Ernst

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923197615&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923197615&partnerID=8YFLogxK

U2 - 10.1038/ncomms7220

DO - 10.1038/ncomms7220

M3 - Article

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6220

ER -