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Uridine-derived ribose fuels glucose-restricted pancreatic cancer
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy(1,2). This is mediated in part by a complex tumour microenvironment(3), low vascularity(4), and metabolic aberrations(5,6). Although altered metabolism drives tumour progression, the spectrum of metabolites u...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232363/ https://www.ncbi.nlm.nih.gov/pubmed/37198494 http://dx.doi.org/10.1038/s41586-023-06073-w |
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author | Nwosu, Zeribe C. Ward, Matthew H. Sajjakulnukit, Peter Poudel, Pawan Ragulan, Chanthirika Kasperek, Steven Radyk, Megan Sutton, Damien Menjivar, Rosa E. Andren, Anthony Apiz-Saab, Juan J. Tolstyka, Zachary Brown, Kristee Lee, Ho-Joon Dzierozynski, Lindsey N. He, Xi PS, Hari Ugras, Julia Nyamundanda, Gift Zhang, Li Halbrook, Christopher J. Carpenter, Eileen S. Shi, Jiaqi Shriver, Leah P. Patti, Gary J. Muir, Alexander Pasca di Magliano, Marina Sadanandam, Anguraj Lyssiotis, Costas A. |
author_facet | Nwosu, Zeribe C. Ward, Matthew H. Sajjakulnukit, Peter Poudel, Pawan Ragulan, Chanthirika Kasperek, Steven Radyk, Megan Sutton, Damien Menjivar, Rosa E. Andren, Anthony Apiz-Saab, Juan J. Tolstyka, Zachary Brown, Kristee Lee, Ho-Joon Dzierozynski, Lindsey N. He, Xi PS, Hari Ugras, Julia Nyamundanda, Gift Zhang, Li Halbrook, Christopher J. Carpenter, Eileen S. Shi, Jiaqi Shriver, Leah P. Patti, Gary J. Muir, Alexander Pasca di Magliano, Marina Sadanandam, Anguraj Lyssiotis, Costas A. |
author_sort | Nwosu, Zeribe C. |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy(1,2). This is mediated in part by a complex tumour microenvironment(3), low vascularity(4), and metabolic aberrations(5,6). Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy. |
format | Online Article Text |
id | pubmed-10232363 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102323632023-06-02 Uridine-derived ribose fuels glucose-restricted pancreatic cancer Nwosu, Zeribe C. Ward, Matthew H. Sajjakulnukit, Peter Poudel, Pawan Ragulan, Chanthirika Kasperek, Steven Radyk, Megan Sutton, Damien Menjivar, Rosa E. Andren, Anthony Apiz-Saab, Juan J. Tolstyka, Zachary Brown, Kristee Lee, Ho-Joon Dzierozynski, Lindsey N. He, Xi PS, Hari Ugras, Julia Nyamundanda, Gift Zhang, Li Halbrook, Christopher J. Carpenter, Eileen S. Shi, Jiaqi Shriver, Leah P. Patti, Gary J. Muir, Alexander Pasca di Magliano, Marina Sadanandam, Anguraj Lyssiotis, Costas A. Nature Article Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy(1,2). This is mediated in part by a complex tumour microenvironment(3), low vascularity(4), and metabolic aberrations(5,6). Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy. Nature Publishing Group UK 2023-05-17 2023 /pmc/articles/PMC10232363/ /pubmed/37198494 http://dx.doi.org/10.1038/s41586-023-06073-w Text en © The Author(s) 2023 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 Nwosu, Zeribe C. Ward, Matthew H. Sajjakulnukit, Peter Poudel, Pawan Ragulan, Chanthirika Kasperek, Steven Radyk, Megan Sutton, Damien Menjivar, Rosa E. Andren, Anthony Apiz-Saab, Juan J. Tolstyka, Zachary Brown, Kristee Lee, Ho-Joon Dzierozynski, Lindsey N. He, Xi PS, Hari Ugras, Julia Nyamundanda, Gift Zhang, Li Halbrook, Christopher J. Carpenter, Eileen S. Shi, Jiaqi Shriver, Leah P. Patti, Gary J. Muir, Alexander Pasca di Magliano, Marina Sadanandam, Anguraj Lyssiotis, Costas A. Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title | Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title_full | Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title_fullStr | Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title_full_unstemmed | Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title_short | Uridine-derived ribose fuels glucose-restricted pancreatic cancer |
title_sort | uridine-derived ribose fuels glucose-restricted pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232363/ https://www.ncbi.nlm.nih.gov/pubmed/37198494 http://dx.doi.org/10.1038/s41586-023-06073-w |
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