High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1breast cancer cells

Vesa Hongisto (Corresponding Author), Sandra Jernström, Vidal Fey, John-Patrick Mpindi, Kristine Kleivi Sahlberg, Olli Kallioniemi, Merja Perälä

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Abstract

The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional monolayers on plastic. However, many cellular features are impaired in these artificial conditions, and large changes in gene expression compared to tumors have been reported. Three-dimensional cell culture models have become increasingly popular and are suggested to be better models than two-dimensional monolayers due to improved cell-to-cell contact and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput three-dimensional drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in two dimensions, in poly(2-hydroxyethyl methacrylate) induced anchorage-independent three-dimensional models, and in Matrigel three-dimensional cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating, or they were allowed to grow in three-dimensional cultures for 4 days before the drug treatment. Large variations in drug responses were observed between the models indicating that comparisons of culture model-influenced drug sensitivities cannot be made based on the effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in two-dimensional cultures, while the responses of cells grown in poly(2-hydroxyethyl methacrylate) resembled those of the two-dimensional cultures. Furthermore, comparing the gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study, we also suggest that three-dimensional cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives to traditional two-dimensional screens for better comparability to the in vivo state.
Original languageEnglish
Article numbere77232
JournalPLoS ONE
Volume8
Issue number10
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Cell culture
Screening
Cells
Throughput
screening
drugs
Pharmaceutical Preparations
Neoplasms
cell culture
cells
Cell Culture Techniques
Heterografts
Gene expression
Tumors
Monolayers
Drug therapy
gene expression
neoplasms
Cultured Tumor Cells
Cell proliferation

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Hongisto, V., Jernström, S., Fey, V., Mpindi, J-P., Kleivi Sahlberg, K., Kallioniemi, O., & Perälä, M. (2013). High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1breast cancer cells. PLoS ONE, 8(10), [e77232]. https://doi.org/10.1371/journal.pone.0077232
Hongisto, Vesa ; Jernström, Sandra ; Fey, Vidal ; Mpindi, John-Patrick ; Kleivi Sahlberg, Kristine ; Kallioniemi, Olli ; Perälä, Merja. / High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1breast cancer cells. In: PLoS ONE. 2013 ; Vol. 8, No. 10.
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abstract = "The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional monolayers on plastic. However, many cellular features are impaired in these artificial conditions, and large changes in gene expression compared to tumors have been reported. Three-dimensional cell culture models have become increasingly popular and are suggested to be better models than two-dimensional monolayers due to improved cell-to-cell contact and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput three-dimensional drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in two dimensions, in poly(2-hydroxyethyl methacrylate) induced anchorage-independent three-dimensional models, and in Matrigel three-dimensional cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating, or they were allowed to grow in three-dimensional cultures for 4 days before the drug treatment. Large variations in drug responses were observed between the models indicating that comparisons of culture model-influenced drug sensitivities cannot be made based on the effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in two-dimensional cultures, while the responses of cells grown in poly(2-hydroxyethyl methacrylate) resembled those of the two-dimensional cultures. Furthermore, comparing the gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study, we also suggest that three-dimensional cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives to traditional two-dimensional screens for better comparability to the in vivo state.",
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Hongisto, V, Jernström, S, Fey, V, Mpindi, J-P, Kleivi Sahlberg, K, Kallioniemi, O & Perälä, M 2013, 'High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1breast cancer cells', PLoS ONE, vol. 8, no. 10, e77232. https://doi.org/10.1371/journal.pone.0077232

High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1breast cancer cells. / Hongisto, Vesa (Corresponding Author); Jernström, Sandra; Fey, Vidal; Mpindi, John-Patrick; Kleivi Sahlberg, Kristine; Kallioniemi, Olli; Perälä, Merja.

In: PLoS ONE, Vol. 8, No. 10, e77232, 2013.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Hongisto, Vesa

AU - Jernström, Sandra

AU - Fey, Vidal

AU - Mpindi, John-Patrick

AU - Kleivi Sahlberg, Kristine

AU - Kallioniemi, Olli

AU - Perälä, Merja

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AB - The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional monolayers on plastic. However, many cellular features are impaired in these artificial conditions, and large changes in gene expression compared to tumors have been reported. Three-dimensional cell culture models have become increasingly popular and are suggested to be better models than two-dimensional monolayers due to improved cell-to-cell contact and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput three-dimensional drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in two dimensions, in poly(2-hydroxyethyl methacrylate) induced anchorage-independent three-dimensional models, and in Matrigel three-dimensional cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating, or they were allowed to grow in three-dimensional cultures for 4 days before the drug treatment. Large variations in drug responses were observed between the models indicating that comparisons of culture model-influenced drug sensitivities cannot be made based on the effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in two-dimensional cultures, while the responses of cells grown in poly(2-hydroxyethyl methacrylate) resembled those of the two-dimensional cultures. Furthermore, comparing the gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study, we also suggest that three-dimensional cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives to traditional two-dimensional screens for better comparability to the in vivo state.

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