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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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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. |
format | Online Article Text |
id | pubmed-8976067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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