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High-content microscopy reveals a morphological signature of bortezomib resistance

Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, that is, possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance...

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Autores principales: Kelley, Megan E, Berman, Adi Y, Stirling, David R, Cimini, Beth A, Han, Yu, Singh, Shantanu, Carpenter, Anne E, Kapoor, Tarun M, Way, Gregory P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584373/
https://www.ncbi.nlm.nih.gov/pubmed/37753907
http://dx.doi.org/10.7554/eLife.91362
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author Kelley, Megan E
Berman, Adi Y
Stirling, David R
Cimini, Beth A
Han, Yu
Singh, Shantanu
Carpenter, Anne E
Kapoor, Tarun M
Way, Gregory P
author_facet Kelley, Megan E
Berman, Adi Y
Stirling, David R
Cimini, Beth A
Han, Yu
Singh, Shantanu
Carpenter, Anne E
Kapoor, Tarun M
Way, Gregory P
author_sort Kelley, Megan E
collection PubMed
description Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, that is, possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug resistance. To test this hypothesis, we used HCT116 cells, a mismatch repair-deficient cancer cell line, to isolate clones that were resistant or sensitive to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then expanded these clones and measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features that differed between resistant and sensitive cells. We used these features to generate a morphological signature of bortezomib resistance. We then employed this morphological signature to analyze a set of HCT116 clones (five resistant and five sensitive) that had not been included in the signature training dataset, and correctly predicted sensitivity to bortezomib in seven cases, in the absence of drug treatment. This signature predicted bortezomib resistance better than resistance to other drugs targeting the ubiquitin-proteasome system, indicating specificity for mechanisms of resistance to bortezomib. Our results establish a proof-of-concept framework for the unbiased analysis of drug resistance using high-content microscopy of cancer cells, in the absence of drug treatment.
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spelling pubmed-105843732023-10-19 High-content microscopy reveals a morphological signature of bortezomib resistance Kelley, Megan E Berman, Adi Y Stirling, David R Cimini, Beth A Han, Yu Singh, Shantanu Carpenter, Anne E Kapoor, Tarun M Way, Gregory P eLife Cancer Biology Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, that is, possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug resistance. To test this hypothesis, we used HCT116 cells, a mismatch repair-deficient cancer cell line, to isolate clones that were resistant or sensitive to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then expanded these clones and measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features that differed between resistant and sensitive cells. We used these features to generate a morphological signature of bortezomib resistance. We then employed this morphological signature to analyze a set of HCT116 clones (five resistant and five sensitive) that had not been included in the signature training dataset, and correctly predicted sensitivity to bortezomib in seven cases, in the absence of drug treatment. This signature predicted bortezomib resistance better than resistance to other drugs targeting the ubiquitin-proteasome system, indicating specificity for mechanisms of resistance to bortezomib. Our results establish a proof-of-concept framework for the unbiased analysis of drug resistance using high-content microscopy of cancer cells, in the absence of drug treatment. eLife Sciences Publications, Ltd 2023-09-27 /pmc/articles/PMC10584373/ /pubmed/37753907 http://dx.doi.org/10.7554/eLife.91362 Text en © 2023, Kelley et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Kelley, Megan E
Berman, Adi Y
Stirling, David R
Cimini, Beth A
Han, Yu
Singh, Shantanu
Carpenter, Anne E
Kapoor, Tarun M
Way, Gregory P
High-content microscopy reveals a morphological signature of bortezomib resistance
title High-content microscopy reveals a morphological signature of bortezomib resistance
title_full High-content microscopy reveals a morphological signature of bortezomib resistance
title_fullStr High-content microscopy reveals a morphological signature of bortezomib resistance
title_full_unstemmed High-content microscopy reveals a morphological signature of bortezomib resistance
title_short High-content microscopy reveals a morphological signature of bortezomib resistance
title_sort high-content microscopy reveals a morphological signature of bortezomib resistance
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584373/
https://www.ncbi.nlm.nih.gov/pubmed/37753907
http://dx.doi.org/10.7554/eLife.91362
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