TY - JOUR
T1 - Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
AU - Wu, Yige
AU - Terekhanova, Nadezhda V.
AU - Caravan, Wagma
AU - Naser Al Deen, Nataly
AU - Lal, Preet
AU - Chen, Siqi
AU - Mo, Chia Kuei
AU - Cao, Song
AU - Li, Yize
AU - Karpova, Alla
AU - Liu, Ruiyang
AU - Zhao, Yanyan
AU - Shinkle, Andrew
AU - Strunilin, Ilya
AU - Weimholt, Cody
AU - Sato, Kazuhito
AU - Yao, Lijun
AU - Serasanambati, Mamatha
AU - Yang, Xiaolu
AU - Wyczalkowski, Matthew
AU - Zhu, Houxiang
AU - Zhou, Daniel Cui
AU - Jayasinghe, Reyka G.
AU - Mendez, Daniel
AU - Wendl, Michael C.
AU - Clark, David
AU - Newton, Chelsea
AU - Ruan, Yijun
AU - Reimers, Melissa A.
AU - Pachynski, Russell K.
AU - Kinsinger, Chris
AU - Jewell, Scott
AU - Chan, Daniel W.
AU - Zhang, Hui
AU - Chaudhuri, Aadel A.
AU - Chheda, Milan G.
AU - Humphreys, Benjamin D.
AU - Mesri, Mehdi
AU - Rodriguez, Henry
AU - Hsieh, James J.
AU - Ding, Li
AU - Chen, Feng
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-023-37211-7
DO - 10.1038/s41467-023-37211-7
M3 - Article
C2 - 36973268
AN - SCOPUS:85150962424
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1681
ER -