Nature Communications (Mar 2023)
Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
- 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
Affiliations
- Yige Wu
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Nadezhda V. Terekhanova
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Wagma Caravan
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Nataly Naser Al Deen
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Preet Lal
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Siqi Chen
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Chia-Kuei Mo
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Song Cao
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Yize Li
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Alla Karpova
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Ruiyang Liu
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Yanyan Zhao
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Andrew Shinkle
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Ilya Strunilin
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Cody Weimholt
- Department of Pathology and Immunology, Washington University in St. Louis
- Kazuhito Sato
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Lijun Yao
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Mamatha Serasanambati
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Xiaolu Yang
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Matthew Wyczalkowski
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Houxiang Zhu
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Daniel Cui Zhou
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Reyka G. Jayasinghe
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Daniel Mendez
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Michael C. Wendl
- Oncology Division, Department of Medicine, Washington University in St. Louis
- David Clark
- Department of Pathology, Johns Hopkins University
- Chelsea Newton
- Van Andel Institutes
- Yijun Ruan
- The Jackson Laboratory for Genomic Medicine
- Melissa A. Reimers
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Russell K. Pachynski
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Chris Kinsinger
- Office of Cancer Clinical Proteomics Research, National Cancer Institute
- Scott Jewell
- Van Andel Institutes
- Daniel W. Chan
- Department of Pathology, Johns Hopkins University
- Hui Zhang
- Department of Pathology, Johns Hopkins University
- Aadel A. Chaudhuri
- Department of Genetics, Washington University in St. Louis
- Milan G. Chheda
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Benjamin D. Humphreys
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute
- Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute
- James J. Hsieh
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Li Ding
- Oncology Division, Department of Medicine, Washington University in St. Louis
- Feng Chen
- Oncology Division, Department of Medicine, Washington University in St. Louis
- DOI
- https://doi.org/10.1038/s41467-023-37211-7
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 25
Abstract
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.
