Document Type
Article
Publication Date
3-27-2023
Original Citation
Wu Y,
Terekhanova N,
Caravan W,
Naser Al Deen N,
Lal P,
Chen S,
Mo C,
Cao S,
Li Y,
Karpova A,
Liu R,
Zhao Y,
Shinkle A,
Strunilin I,
Weimholt C,
Sato K,
Yao L,
Serasanambati M,
Yang X,
Wyczalkowski M,
Zhu H,
Zhou D,
Jayasinghe R,
Mendez D,
Wendl M,
Clark D,
Newton C,
Ruan Y,
Reimers M,
Pachynski R,
Kinsinger C,
Jewell S,
Chan D,
Zhang H,
Chaudhuri A,
Chheda M,
Humphreys B,
Mesri M,
Rodriguez H,
Hsieh J,
Ding L,
Chen F.
Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma. Nat Commun. 2023;14(1):1681
Keywords
JGM, Humans, Carcinoma, Renal Cell, Kidney Neoplasms, Transcriptome, Epigenesis, Genetic, Tumor Suppressor Proteins, Gene Expression Regulation, Neoplastic
JAX Source
Nat Commun. 2023;14(1):1681
ISSN
2041-1723
PMID
36973268
DOI
https://doi.org/10.1038/s41467-023-37211-7
Grant
This work was done in collaboration with the U.S. National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) and supported by the NCI R01HG009711 (L.D., F.C.), U24CA211006 (L.D.), U2CCA233303 (L.D.), and U24CA210972 (L.D.) Funds.
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.
Comments
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