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.
Highlights
Papillary renal cell carcinoma is the most heterogenous renal cell carcinoma
We find that Papillary renal cell carcinoma (pRCC) with different cell-of-origin have different molecular characteristics, undergo different carcinogenic transformations, and display different clinical behaviors. pRCC show cell-oforigin-dependent risks of progression, which is characterized by metabolism reprogramming. pRCC that originated from collecting duct principal cells (CD_PC) are enriched for advanced pRCC and activated interferon signaling, suggesting their potential response to checkpoint immunotherapy
Our study demonstrates that the chromatin accessibility landscape is a potential early diagnostic method for advanced pRCC, allowing cell-of-origin dependent molecular characteristics to direct the treatment of pRCC
Summary
Papillary renal cell carcinoma (pRCC) is the most heterogenous renal cell carcinoma. Patient survival varies and no effective therapies for advanced pRCC exist. Recent studies identified the proximal tubule (PT) cell as a cell-of-origin for pRCC It remains elusive whether other pRCC subtypes have different cell-of-origin. From histological and molecular characterization studies, we know pRCC tumors are highly heterogenous and display various subtypes with different malignancies, making the disease extremely difficult to treat[1,2,3,4]. Stable and heritable epigenetic signatures such as transcription factors programs[15], histone modifications[16] and DNA methylation[17] have been used effectively to trace the cell-of-origin and subtypes of morphological and molecular evolving tumor cells. Our study demonstrates that the chromatin accessibility landscape is a potential early diagnostic method for advanced pRCC, allowing cell-of-origin dependent molecular characteristics to direct the treatment of pRCC
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