Wilms tumors arise from fetal cells whereas adult tumors arise from proximal convoluted tubular cells.
Major finding: Wilms tumors arise from fetal cells whereas adult tumors arise from proximal convoluted tubular cells.
Approach: Single-cell RNA sequencing of 72,501 cells reveals the composition of pediatric and adult kidney tumors.
Impact: Single-cell RNA-seq provides a strategy for determining the molecular identity of human cancer cells.
The cellular origins of human kidney cancers are not well defined. To characterize normal and cancerous human kidney cells, Young, Mitchell, Vieira Braga, and colleagues performed single-cell RNA sequencing (RNA-seq) of 72,501 kidney cells derived from Wilms tumors (3 specimens), clear cell renal cell carcinoma (ccRCC; 3 specimens), papillary renal cell carcinoma (pRCC; 1 specimen), and healthy fetal (2 specimens), pediatric (3 specimens), adolescent (2 specimens), and adult (5 specimens) kidneys, as well as ureters (4 specimens). A total of 29,692 of the sequenced cells were extracted from tumors, and 42,809 were extracted from normal tissue. The transcriptome data allowed segregation of cells into distinct clusters based on gene expression pattern and generation of a reference map to distinguish between normal mature and fetal cells. Comparison of the single-cell landscape of healthy kidney cells versus the tumor cells revealed that Wilms tumor cells resembled normal fetal cells, specifically matching either the ureteric bud or primitive vesicle cells in the developing nephron, suggesting that Wilms tumor arises from aberrant fetal cells. In contrast, cells from the adult tumors, ccRCC and pRCC, had the transcriptional features of a specific subtype of convoluted proximal tubular cells defined by expression of SLC17A3 and VCAM1 and lack of expression of SLC7A13, representing the likely cell of origin for ccRCC and pRCC. Further, the RCC cells secreted VEGFA into the tumor microenvironment to elicit a response from the endothelial cells, and tumor-infiltrating macrophages served as an additional source of VEGFA. Altogether, single-cell RNA-seq revealed the cellular composition of kidney tumors and showed that pediatric and adult tumors arise from distinct cells of origin.
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