Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time

Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known ab...

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Autores principales: Xu, Tong, Junge, Jason A., Delfarah, Alireza, Lu, Yi-Tsung, Arnesano, Cosimo, Iqbal, Maheen, Delijani, Kevin, Hsieh, Tien-Chan, Hodara, Emmanuelle, Mehta, Hemal H., Cohen, Pinchas, Graham, Nicholas A., Fraser, Scott E., Goldkorn, Amir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976067/
https://www.ncbi.nlm.nih.gov/pubmed/35365706
http://dx.doi.org/10.1038/s41598-022-09438-9
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author Xu, Tong
Junge, Jason A.
Delfarah, Alireza
Lu, Yi-Tsung
Arnesano, Cosimo
Iqbal, Maheen
Delijani, Kevin
Hsieh, Tien-Chan
Hodara, Emmanuelle
Mehta, Hemal H.
Cohen, Pinchas
Graham, Nicholas A.
Fraser, Scott E.
Goldkorn, Amir
author_facet Xu, Tong
Junge, Jason A.
Delfarah, Alireza
Lu, Yi-Tsung
Arnesano, Cosimo
Iqbal, Maheen
Delijani, Kevin
Hsieh, Tien-Chan
Hodara, Emmanuelle
Mehta, Hemal H.
Cohen, Pinchas
Graham, Nicholas A.
Fraser, Scott E.
Goldkorn, Amir
author_sort Xu, Tong
collection PubMed
description Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.
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spelling pubmed-89760672022-04-05 Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time Xu, Tong Junge, Jason A. Delfarah, Alireza Lu, Yi-Tsung Arnesano, Cosimo Iqbal, Maheen Delijani, Kevin Hsieh, Tien-Chan Hodara, Emmanuelle Mehta, Hemal H. Cohen, Pinchas Graham, Nicholas A. Fraser, Scott E. Goldkorn, Amir Sci Rep Article Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance. Nature Publishing Group UK 2022-04-01 /pmc/articles/PMC8976067/ /pubmed/35365706 http://dx.doi.org/10.1038/s41598-022-09438-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Xu, Tong
Junge, Jason A.
Delfarah, Alireza
Lu, Yi-Tsung
Arnesano, Cosimo
Iqbal, Maheen
Delijani, Kevin
Hsieh, Tien-Chan
Hodara, Emmanuelle
Mehta, Hemal H.
Cohen, Pinchas
Graham, Nicholas A.
Fraser, Scott E.
Goldkorn, Amir
Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title_full Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title_fullStr Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title_full_unstemmed Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title_short Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
title_sort bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976067/
https://www.ncbi.nlm.nih.gov/pubmed/35365706
http://dx.doi.org/10.1038/s41598-022-09438-9
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