Single-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma

Qi Wang, Yang Zhang, Bolei Zhang, Yao Fu, Xiaozhi Zhao, Jing Zhang, Ke Zuo, Yuexian Xing, Song Jiang, Zhaohui Qin, Erguang Li, Hongqian Guo (), Zhihong Liu () and Jingping Yang ()
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Qi Wang: Medical School of Nanjing University
Yang Zhang: Medical School of Nanjing University
Bolei Zhang: School of Computer Science, Nanjing University of Posts and Telecommunications
Yao Fu: Medical School of Nanjing University
Xiaozhi Zhao: Medical School of Nanjing University
Jing Zhang: Medical School of Nanjing University
Ke Zuo: Medical School of Nanjing University
Yuexian Xing: Medical School of Nanjing University
Song Jiang: Medical School of Nanjing University
Zhaohui Qin: Emory University
Erguang Li: Medical School of Nanjing University
Hongqian Guo: Medical School of Nanjing University
Zhihong Liu: Medical School of Nanjing University
Jingping Yang: Medical School of Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Papillary renal cell carcinoma (pRCC) is the most heterogenous renal cell carcinoma. Patient survival varies and no effective therapies for advanced pRCC exist. Histological and molecular characterization studies have highlighted the heterogeneity of pRCC tumours. Recent studies identified the proximal tubule (PT) cell as a cell-of-origin for pRCC. However, it remains elusive whether other pRCC subtypes have different cell-of-origin. Here, by obtaining genome-wide chromatin accessibility profiles of normal human kidney cells using single-cell transposase-accessible chromatin-sequencing and comparing the profiles with pRCC samples, we discover that besides PT cells, pRCC can also originate from kidney collecting duct principal cells. We show pRCCs with different cell-of-origin exhibit different molecular characteristics and clinical behaviors. Further, metabolic reprogramming appears to mediate the progression of pRCC to the advanced state. Here, our results suggest that determining cell-of-origin and monitoring origin-dependent metabolism could potentially be useful for early diagnosis and treatment of pRCC.

Date: 2022
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DOI: 10.1038/s41467-021-27660-3

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