Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
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Published:2023-03-27
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wu Yige, Terekhanova Nadezhda V., Caravan WagmaORCID, Naser Al Deen Nataly, Lal Preet, Chen Siqi, Mo Chia-Kuei, Cao Song, Li YizeORCID, Karpova Alla, Liu Ruiyang, Zhao Yanyan, Shinkle Andrew, Strunilin Ilya, Weimholt Cody, Sato KazuhitoORCID, Yao Lijun, Serasanambati Mamatha, Yang XiaoluORCID, Wyczalkowski MatthewORCID, Zhu Houxiang, Zhou Daniel CuiORCID, Jayasinghe Reyka G.ORCID, Mendez Daniel, Wendl Michael C., Clark David, Newton Chelsea, Ruan Yijun, Reimers Melissa A., Pachynski Russell K., Kinsinger Chris, Jewell ScottORCID, Chan Daniel W., Zhang HuiORCID, Chaudhuri Aadel A.ORCID, Chheda Milan G.ORCID, Humphreys Benjamin D.ORCID, Mesri Mehdi, Rodriguez Henry, Hsieh James J.ORCID, Ding LiORCID, Chen FengORCID
Abstract
AbstractIdentifying 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.CPknockdown, 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,BAP1mutations are associated with widespread reduction of chromatin accessibility, whilePBRM1 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference133 articles.
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