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

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.

Automated summary

Papillary renal cell carcinoma (pRCC) is a highly heterogeneous cancer with varying patient survival. Recent studies have found that pRCC can originate from proximal tubule (PT) cells as well as kidney collecting duct principal cells. Different cell-of-origin for pRCC result in distinct molecular characteristics and clinical behaviors. Metabolic reprogramming may play a role in the progression of pRCC. Determining the cell-of-origin and monitoring origin-dependent metabolism could potentially aid in early diagnosis and treatment of pRCC.