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Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched...

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Autores principales: Wu, Yige, Terekhanova, Nadezhda V., Caravan, Wagma, Naser Al Deen, Nataly, Lal, Preet, Chen, Siqi, Mo, Chia-Kuei, Cao, Song, Li, Yize, Karpova, Alla, Liu, Ruiyang, Zhao, Yanyan, Shinkle, Andrew, Strunilin, Ilya, Weimholt, Cody, Sato, Kazuhito, Yao, Lijun, Serasanambati, Mamatha, Yang, Xiaolu, Wyczalkowski, Matthew, Zhu, Houxiang, Zhou, Daniel Cui, Jayasinghe, Reyka G., Mendez, Daniel, Wendl, Michael C., Clark, David, Newton, Chelsea, Ruan, Yijun, Reimers, Melissa A., Pachynski, Russell K., Kinsinger, Chris, Jewell, Scott, Chan, Daniel W., Zhang, Hui, Chaudhuri, Aadel A., Chheda, Milan G., Humphreys, Benjamin D., Mesri, Mehdi, Rodriguez, Henry, Hsieh, James J., Ding, Li, Chen, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042888/
https://www.ncbi.nlm.nih.gov/pubmed/36973268
http://dx.doi.org/10.1038/s41467-023-37211-7
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author Wu, Yige
Terekhanova, Nadezhda V.
Caravan, Wagma
Naser Al Deen, Nataly
Lal, Preet
Chen, Siqi
Mo, Chia-Kuei
Cao, Song
Li, Yize
Karpova, Alla
Liu, Ruiyang
Zhao, Yanyan
Shinkle, Andrew
Strunilin, Ilya
Weimholt, Cody
Sato, Kazuhito
Yao, Lijun
Serasanambati, Mamatha
Yang, Xiaolu
Wyczalkowski, Matthew
Zhu, Houxiang
Zhou, Daniel Cui
Jayasinghe, Reyka G.
Mendez, Daniel
Wendl, Michael C.
Clark, David
Newton, Chelsea
Ruan, Yijun
Reimers, Melissa A.
Pachynski, Russell K.
Kinsinger, Chris
Jewell, Scott
Chan, Daniel W.
Zhang, Hui
Chaudhuri, Aadel A.
Chheda, Milan G.
Humphreys, Benjamin D.
Mesri, Mehdi
Rodriguez, Henry
Hsieh, James J.
Ding, Li
Chen, Feng
author_facet Wu, Yige
Terekhanova, Nadezhda V.
Caravan, Wagma
Naser Al Deen, Nataly
Lal, Preet
Chen, Siqi
Mo, Chia-Kuei
Cao, Song
Li, Yize
Karpova, Alla
Liu, Ruiyang
Zhao, Yanyan
Shinkle, Andrew
Strunilin, Ilya
Weimholt, Cody
Sato, Kazuhito
Yao, Lijun
Serasanambati, Mamatha
Yang, Xiaolu
Wyczalkowski, Matthew
Zhu, Houxiang
Zhou, Daniel Cui
Jayasinghe, Reyka G.
Mendez, Daniel
Wendl, Michael C.
Clark, David
Newton, Chelsea
Ruan, Yijun
Reimers, Melissa A.
Pachynski, Russell K.
Kinsinger, Chris
Jewell, Scott
Chan, Daniel W.
Zhang, Hui
Chaudhuri, Aadel A.
Chheda, Milan G.
Humphreys, Benjamin D.
Mesri, Mehdi
Rodriguez, Henry
Hsieh, James J.
Ding, Li
Chen, Feng
author_sort Wu, Yige
collection PubMed
description Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.
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spelling pubmed-100428882023-03-29 Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma Wu, Yige Terekhanova, Nadezhda V. Caravan, Wagma Naser Al Deen, Nataly Lal, Preet Chen, Siqi Mo, Chia-Kuei Cao, Song Li, Yize Karpova, Alla Liu, Ruiyang Zhao, Yanyan Shinkle, Andrew Strunilin, Ilya Weimholt, Cody Sato, Kazuhito Yao, Lijun Serasanambati, Mamatha Yang, Xiaolu Wyczalkowski, Matthew Zhu, Houxiang Zhou, Daniel Cui Jayasinghe, Reyka G. Mendez, Daniel Wendl, Michael C. Clark, David Newton, Chelsea Ruan, Yijun Reimers, Melissa A. Pachynski, Russell K. Kinsinger, Chris Jewell, Scott Chan, Daniel W. Zhang, Hui Chaudhuri, Aadel A. Chheda, Milan G. Humphreys, Benjamin D. Mesri, Mehdi Rodriguez, Henry Hsieh, James J. Ding, Li Chen, Feng Nat Commun Article Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis. Nature Publishing Group UK 2023-03-27 /pmc/articles/PMC10042888/ /pubmed/36973268 http://dx.doi.org/10.1038/s41467-023-37211-7 Text en © The Author(s) 2023, corrected publication 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wu, Yige
Terekhanova, Nadezhda V.
Caravan, Wagma
Naser Al Deen, Nataly
Lal, Preet
Chen, Siqi
Mo, Chia-Kuei
Cao, Song
Li, Yize
Karpova, Alla
Liu, Ruiyang
Zhao, Yanyan
Shinkle, Andrew
Strunilin, Ilya
Weimholt, Cody
Sato, Kazuhito
Yao, Lijun
Serasanambati, Mamatha
Yang, Xiaolu
Wyczalkowski, Matthew
Zhu, Houxiang
Zhou, Daniel Cui
Jayasinghe, Reyka G.
Mendez, Daniel
Wendl, Michael C.
Clark, David
Newton, Chelsea
Ruan, Yijun
Reimers, Melissa A.
Pachynski, Russell K.
Kinsinger, Chris
Jewell, Scott
Chan, Daniel W.
Zhang, Hui
Chaudhuri, Aadel A.
Chheda, Milan G.
Humphreys, Benjamin D.
Mesri, Mehdi
Rodriguez, Henry
Hsieh, James J.
Ding, Li
Chen, Feng
Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title_full Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title_fullStr Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title_full_unstemmed Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title_short Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
title_sort epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042888/
https://www.ncbi.nlm.nih.gov/pubmed/36973268
http://dx.doi.org/10.1038/s41467-023-37211-7
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