Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Yige Wu, Washington University School of Medicine in St. Louis
Nadezhda V. Terekhanova, Washington University School of Medicine in St. Louis
Wagma Caravan, Washington University School of Medicine in St. Louis
Nataly Naser Al Deen, Washington University School of Medicine in St. Louis
Preet Lal, Washington University School of Medicine in St. Louis
Siqi Chen, Washington University School of Medicine in St. Louis
Chia Kuei Mo, Washington University School of Medicine in St. Louis
Song Cao, Washington University School of Medicine in St. Louis
Yize Li, Washington University School of Medicine in St. Louis
Alla Karpova, Washington University School of Medicine in St. Louis
Ruiyang Liu, Washington University School of Medicine in St. Louis
Yanyan Zhao, Washington University School of Medicine in St. Louis
Andrew Shinkle, Washington University School of Medicine in St. Louis
Ilya Strunilin, Washington University School of Medicine in St. Louis
Cody Weimholt, Washington University School of Medicine in St. Louis
Kazuhito Sato, Washington University School of Medicine in St. Louis
Lijun Yao, Washington University School of Medicine in St. Louis
Mamatha Serasanambati, Washington University School of Medicine in St. Louis
Xiaolu Yang, Washington University School of Medicine in St. Louis
Matthew Wyczalkowski, Washington University School of Medicine in St. Louis
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.
