Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Abstract 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, wit...
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| Format: | Article |
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Nature Portfolio
2023-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37211-7 |
| _version_ | 1797822845815881728 |
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| author | Yige Wu Nadezhda V. Terekhanova Wagma Caravan Nataly Naser Al Deen Preet Lal Siqi Chen Chia-Kuei Mo Song Cao Yize Li Alla Karpova Ruiyang Liu Yanyan Zhao Andrew Shinkle Ilya Strunilin Cody Weimholt Kazuhito Sato Lijun Yao Mamatha Serasanambati Xiaolu Yang Matthew Wyczalkowski Houxiang Zhu Daniel Cui Zhou Reyka G. Jayasinghe Daniel Mendez Michael C. Wendl David Clark Chelsea Newton Yijun Ruan Melissa A. Reimers Russell K. Pachynski Chris Kinsinger Scott Jewell Daniel W. Chan Hui Zhang Aadel A. Chaudhuri Milan G. Chheda Benjamin D. Humphreys Mehdi Mesri Henry Rodriguez James J. Hsieh Li Ding Feng Chen |
| author_facet | Yige Wu Nadezhda V. Terekhanova Wagma Caravan Nataly Naser Al Deen Preet Lal Siqi Chen Chia-Kuei Mo Song Cao Yize Li Alla Karpova Ruiyang Liu Yanyan Zhao Andrew Shinkle Ilya Strunilin Cody Weimholt Kazuhito Sato Lijun Yao Mamatha Serasanambati Xiaolu Yang Matthew Wyczalkowski Houxiang Zhu Daniel Cui Zhou Reyka G. Jayasinghe Daniel Mendez Michael C. Wendl David Clark Chelsea Newton Yijun Ruan Melissa A. Reimers Russell K. Pachynski Chris Kinsinger Scott Jewell Daniel W. Chan Hui Zhang Aadel A. Chaudhuri Milan G. Chheda Benjamin D. Humphreys Mehdi Mesri Henry Rodriguez James J. Hsieh Li Ding Feng Chen |
| author_sort | Yige Wu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T10:15:19Z |
| format | Article |
| id | doaj.art-f1e225c958cf48d29abdb4ad3857630a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:15:19Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f1e225c958cf48d29abdb4ad3857630a2023-05-21T11:19:50ZengNature PortfolioNature Communications2041-17232023-03-0114112510.1038/s41467-023-37211-7Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinomaYige Wu0Nadezhda V. Terekhanova1Wagma Caravan2Nataly Naser Al Deen3Preet Lal4Siqi Chen5Chia-Kuei Mo6Song Cao7Yize Li8Alla Karpova9Ruiyang Liu10Yanyan Zhao11Andrew Shinkle12Ilya Strunilin13Cody Weimholt14Kazuhito Sato15Lijun Yao16Mamatha Serasanambati17Xiaolu Yang18Matthew Wyczalkowski19Houxiang Zhu20Daniel Cui Zhou21Reyka G. Jayasinghe22Daniel Mendez23Michael C. Wendl24David Clark25Chelsea Newton26Yijun Ruan27Melissa A. Reimers28Russell K. Pachynski29Chris Kinsinger30Scott Jewell31Daniel W. Chan32Hui Zhang33Aadel A. Chaudhuri34Milan G. Chheda35Benjamin D. Humphreys36Mehdi Mesri37Henry Rodriguez38James J. Hsieh39Li Ding40Feng Chen41Oncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisDepartment of Pathology and Immunology, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisDepartment of Pathology, Johns Hopkins UniversityVan Andel InstitutesThe Jackson Laboratory for Genomic MedicineOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOffice of Cancer Clinical Proteomics Research, National Cancer InstituteVan Andel InstitutesDepartment of Pathology, Johns Hopkins UniversityDepartment of Pathology, Johns Hopkins UniversityDepartment of Genetics, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOffice of Cancer Clinical Proteomics Research, National Cancer InstituteOffice of Cancer Clinical Proteomics Research, National Cancer InstituteOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisOncology Division, Department of Medicine, Washington University in St. LouisAbstract 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.https://doi.org/10.1038/s41467-023-37211-7 |
| spellingShingle | Yige Wu Nadezhda V. Terekhanova Wagma Caravan Nataly Naser Al Deen Preet Lal Siqi Chen Chia-Kuei Mo Song Cao Yize Li Alla Karpova Ruiyang Liu Yanyan Zhao Andrew Shinkle Ilya Strunilin Cody Weimholt Kazuhito Sato Lijun Yao Mamatha Serasanambati Xiaolu Yang Matthew Wyczalkowski Houxiang Zhu Daniel Cui Zhou Reyka G. Jayasinghe Daniel Mendez Michael C. Wendl David Clark Chelsea Newton Yijun Ruan Melissa A. Reimers Russell K. Pachynski Chris Kinsinger Scott Jewell Daniel W. Chan Hui Zhang Aadel A. Chaudhuri Milan G. Chheda Benjamin D. Humphreys Mehdi Mesri Henry Rodriguez James J. Hsieh Li Ding Feng Chen Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma Nature Communications |
| 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 |
| url | https://doi.org/10.1038/s41467-023-37211-7 |
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