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Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells

Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resi...

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Autores principales: Sayin, Serkan, Rosener, Brittany, Li, Carmen G, Ho, Bao, Ponomarova, Olga, Ward, Doyle V, Walhout, Albertha JM, Mitchell, Amir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931390/
https://www.ncbi.nlm.nih.gov/pubmed/36734518
http://dx.doi.org/10.7554/eLife.83140
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author Sayin, Serkan
Rosener, Brittany
Li, Carmen G
Ho, Bao
Ponomarova, Olga
Ward, Doyle V
Walhout, Albertha JM
Mitchell, Amir
author_facet Sayin, Serkan
Rosener, Brittany
Li, Carmen G
Ho, Bao
Ponomarova, Olga
Ward, Doyle V
Walhout, Albertha JM
Mitchell, Amir
author_sort Sayin, Serkan
collection PubMed
description Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor’s chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria–drug interactions can have local and systemic influence on drug activity.
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spelling pubmed-99313902023-02-16 Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells Sayin, Serkan Rosener, Brittany Li, Carmen G Ho, Bao Ponomarova, Olga Ward, Doyle V Walhout, Albertha JM Mitchell, Amir eLife Computational and Systems Biology Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor’s chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria–drug interactions can have local and systemic influence on drug activity. eLife Sciences Publications, Ltd 2023-02-03 /pmc/articles/PMC9931390/ /pubmed/36734518 http://dx.doi.org/10.7554/eLife.83140 Text en © 2023, Sayin 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 Computational and Systems Biology
Sayin, Serkan
Rosener, Brittany
Li, Carmen G
Ho, Bao
Ponomarova, Olga
Ward, Doyle V
Walhout, Albertha JM
Mitchell, Amir
Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title_full Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title_fullStr Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title_full_unstemmed Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title_short Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
title_sort evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931390/
https://www.ncbi.nlm.nih.gov/pubmed/36734518
http://dx.doi.org/10.7554/eLife.83140
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