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Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer
BACKGROUND: Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and imm...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060625/ https://www.ncbi.nlm.nih.gov/pubmed/37006250 http://dx.doi.org/10.3389/fimmu.2023.1165101 |
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author | Xu, Ximo Ding, Chengsheng Zhong, Hao Qin, Wei Shu, Duohuo Yu, Mengqin Abuduaini, Naijipu Zhang, Sen Yang, Xiao Feng, Bo |
author_facet | Xu, Ximo Ding, Chengsheng Zhong, Hao Qin, Wei Shu, Duohuo Yu, Mengqin Abuduaini, Naijipu Zhang, Sen Yang, Xiao Feng, Bo |
author_sort | Xu, Ximo |
collection | PubMed |
description | BACKGROUND: Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and immune regulation in colorectal cancer (CRC) remains unclear. METHODS: Ten cuprotosis-related genes were selected and unsupervised consensus clustering was performed to identify the cuprotosis patterns and the correlated TME characteristics. Using principal component analysis, a COPsig score was established to quantify cuprotosis patterns in individual patients. The top 9 most important cuprotosis signature genes were analyzed using single-cell transcriptome data. RESULTS: Three distinct cuprotosis patterns were identified. The TME cell infiltration characteristics of three patterns were associated with immune-excluded, immune-desert, and immune-inflamed phenotype, respectively. Based on individual cuprotosis patterns, patients were assigned into high and low COPsig score groups. Patients with a higher COPsig score were characterized by longer overall survival time, lower immune cell as well as stromal infiltration, and greater tumor mutational burden. Moreover, further analysis demonstrated that CRC patients with a higher COPsig score were more likely to respond to immune checkpoint inhibitors and 5-fluorouracil chemotherapy. Single-cell transcriptome analysis indicated that cuprotosis signature genes recruited tumor-associated macrophages to TME through the regulation of TCA and the metabolism of glutamine and fatty acid, thus influencing the prognosis of CRC patients. CONCLUSION: This study indicated that distinct cuprotosis patterns laid a solid foundation to the explanation of heterogeneity and complexity of individual TME, thus guiding more effective immunotherapy as well as adjuvant chemotherapy strategies. |
format | Online Article Text |
id | pubmed-10060625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100606252023-03-31 Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer Xu, Ximo Ding, Chengsheng Zhong, Hao Qin, Wei Shu, Duohuo Yu, Mengqin Abuduaini, Naijipu Zhang, Sen Yang, Xiao Feng, Bo Front Immunol Immunology BACKGROUND: Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and immune regulation in colorectal cancer (CRC) remains unclear. METHODS: Ten cuprotosis-related genes were selected and unsupervised consensus clustering was performed to identify the cuprotosis patterns and the correlated TME characteristics. Using principal component analysis, a COPsig score was established to quantify cuprotosis patterns in individual patients. The top 9 most important cuprotosis signature genes were analyzed using single-cell transcriptome data. RESULTS: Three distinct cuprotosis patterns were identified. The TME cell infiltration characteristics of three patterns were associated with immune-excluded, immune-desert, and immune-inflamed phenotype, respectively. Based on individual cuprotosis patterns, patients were assigned into high and low COPsig score groups. Patients with a higher COPsig score were characterized by longer overall survival time, lower immune cell as well as stromal infiltration, and greater tumor mutational burden. Moreover, further analysis demonstrated that CRC patients with a higher COPsig score were more likely to respond to immune checkpoint inhibitors and 5-fluorouracil chemotherapy. Single-cell transcriptome analysis indicated that cuprotosis signature genes recruited tumor-associated macrophages to TME through the regulation of TCA and the metabolism of glutamine and fatty acid, thus influencing the prognosis of CRC patients. CONCLUSION: This study indicated that distinct cuprotosis patterns laid a solid foundation to the explanation of heterogeneity and complexity of individual TME, thus guiding more effective immunotherapy as well as adjuvant chemotherapy strategies. Frontiers Media S.A. 2023-03-16 /pmc/articles/PMC10060625/ /pubmed/37006250 http://dx.doi.org/10.3389/fimmu.2023.1165101 Text en Copyright © 2023 Xu, Ding, Zhong, Qin, Shu, Yu, Abuduaini, Zhang, Yang and Feng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Xu, Ximo Ding, Chengsheng Zhong, Hao Qin, Wei Shu, Duohuo Yu, Mengqin Abuduaini, Naijipu Zhang, Sen Yang, Xiao Feng, Bo Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title | Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title_full | Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title_fullStr | Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title_full_unstemmed | Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title_short | Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
title_sort | integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060625/ https://www.ncbi.nlm.nih.gov/pubmed/37006250 http://dx.doi.org/10.3389/fimmu.2023.1165101 |
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