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 Y. Karpova, Ruiyang Liu, Yanyan Zhao, Andrew Shinkle, Ilya Strunilin, Cody Weimholt, Kazuhito Sato, Lijun Yao, Mamatha Serasanambati, Xiaolu Yang, Matthew A. Wyczalkowski, Houxiang Zhu, Daniel Cui Zhou, Reyka G. Jayasinghe, Daniel Mendez, Michael C. Wendl, David Clark, Chelsea J. Newton, Yijun Ruan, Melissa A. Reimers, Russell K. Pachynski, Chris Kinsinger, Scott D. 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
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.