Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

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.

A nanoparticle-based sonodynamic therapy reduces Helicobacter pylori infection in mouse without disrupting gut microbiota

“…To identify the bacterial species with significantly changed relative abundances in mouse gut microbiota after the sonodynamic therapy, we analysed the fold of change, a widely used index in such analysis 60 , 61 , in bacterial relative abundance after the sonodynamic therapy relative to the healthy group (i.e., log 2 (Sonodynamic Therapy / Healthy)) (Fig. 7f ) and that relative to the control group (i.e., log 2 (Sonodynamic Therapy / Control)) (Fig.…”

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment

“…High EMT enrichment scores on bulk RNA sequencing are associated with worse disease specific survival in ccRCC 22 , and various EMT ligand-receptor pairs have been implicated. 23, 24,25 Prior spatial transcriptomic work using spot-based resolution has also identified EMT-rich tumor cells being associated with worse prognosis in the TCGA cohort. 26 Still, specific ligand-receptor pairs from the EMT pathway were not elucidated in these studies.…”

The chromatin landscape of healthy and injured cell types in the human kidney

“…In one study, reduced accessibility of glucocorticoid receptor binding sites was observed in the proximal tubule of diabetic humans 15 . Investigations have also examined chromatin accessibility in human Papillary RCC (pRCC), kidney organoid differentiation 5 , 17 , 18 , and in multiple murine models 19 , 20 . Each of these studies provides important insights into epigenetic expression regulation in the kidney.…”