Cargando…

High-content microscopy reveals a morphological signature of bortezomib resistance

Drug resistance is a challenge in anticancer therapy, particularly with targeted therapeutics and cytotoxic compounds. In many cases, cancers can be resistant to the drug prior to exposure, i.e., possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance...

Descripción completa

Detalles Bibliográficos
Autores principales: Kelley, M.E., Berman, A.Y., Stirling, D.R., Cimini, B.A., Han, Y., Singh, S., Carpenter, A.E., Kapoor, T.M., Way, G.P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187224/
https://www.ncbi.nlm.nih.gov/pubmed/37205516
http://dx.doi.org/10.1101/2023.05.02.539137
_version_ 1785042705809670144
author Kelley, M.E.
Berman, A.Y.
Stirling, D.R.
Cimini, B.A.
Han, Y.
Singh, S.
Carpenter, A.E.
Kapoor, T.M.
Way, G.P.
author_facet Kelley, M.E.
Berman, A.Y.
Stirling, D.R.
Cimini, B.A.
Han, Y.
Singh, S.
Carpenter, A.E.
Kapoor, T.M.
Way, G.P.
author_sort Kelley, M.E.
collection PubMed
description Drug resistance is a challenge in anticancer therapy, particularly with targeted therapeutics and cytotoxic compounds. In many cases, cancers can be resistant to the drug prior to exposure, i.e., 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 sensitivity prior to treatment. We therefore isolated clonal cell lines that were either sensitive or resistant to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then 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 typically different between resistant and sensitive clones. These features were compiled to generate a morphological signature of bortezomib resistance, which correctly predicted the bortezomib treatment response in seven of ten cell lines not included in the training dataset. This signature of resistance was specific to bortezomib over other drugs targeting the ubiquitin-proteasome system. Our results provide evidence that intrinsic morphological features of drug resistance exist and establish a framework for their identification.
format Online
Article
Text
id pubmed-10187224
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-101872242023-05-17 High-content microscopy reveals a morphological signature of bortezomib resistance Kelley, M.E. Berman, A.Y. Stirling, D.R. Cimini, B.A. Han, Y. Singh, S. Carpenter, A.E. Kapoor, T.M. Way, G.P. bioRxiv Article Drug resistance is a challenge in anticancer therapy, particularly with targeted therapeutics and cytotoxic compounds. In many cases, cancers can be resistant to the drug prior to exposure, i.e., 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 sensitivity prior to treatment. We therefore isolated clonal cell lines that were either sensitive or resistant to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then 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 typically different between resistant and sensitive clones. These features were compiled to generate a morphological signature of bortezomib resistance, which correctly predicted the bortezomib treatment response in seven of ten cell lines not included in the training dataset. This signature of resistance was specific to bortezomib over other drugs targeting the ubiquitin-proteasome system. Our results provide evidence that intrinsic morphological features of drug resistance exist and establish a framework for their identification. Cold Spring Harbor Laboratory 2023-05-02 /pmc/articles/PMC10187224/ /pubmed/37205516 http://dx.doi.org/10.1101/2023.05.02.539137 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Kelley, M.E.
Berman, A.Y.
Stirling, D.R.
Cimini, B.A.
Han, Y.
Singh, S.
Carpenter, A.E.
Kapoor, T.M.
Way, G.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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187224/
https://www.ncbi.nlm.nih.gov/pubmed/37205516
http://dx.doi.org/10.1101/2023.05.02.539137
work_keys_str_mv AT kelleyme highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT bermanay highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT stirlingdr highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT ciminiba highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT hany highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT singhs highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT carpenterae highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT kapoortm highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance
AT waygp highcontentmicroscopyrevealsamorphologicalsignatureofbortezomibresistance