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.
Highlights
The tumour microenvironment contributes to cancer metastasis and drug resistance
The tumour microenvironment plays an important role in the processes of metastasis and drug resistance[1,2,3,4], yet most drug discovery programmes involving high throughput screening (HTS) use cancer cells cultured in a monolayer twodimensional (2D) on plastic[5,6,7]
All organs in the peritoneal cavity are covered by a single layer of mesothelial cells that rest on a basement membrane of extracellular matrix (ECM) interspersed with fibroblasts (Fig. 1a)[20]
Summary
The tumour microenvironment contributes to cancer metastasis and drug resistance. most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. These compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models 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. The same cells cultured in 3D showed a 10–100-fold reduction in sensitivity to the inhibitor, implying that the cellular context and a 3D environment has an important effect in drug resistance[14,15] These results underscore the importance of performing screens for new drugs using model systems that more faithfully recapitulate tissue architecture at the metastatic site. Our results demonstrate that an in vitro 3D model based on primary cells can be used effectively in HTS and could become an important tool for improving drug screening efficacy
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