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Single-Cell Transcriptome Atlas Elucidates Features Shared by Cancerous, Normal Kidneys

NEW YORK (GenomeWeb) – By performing RNA sequencing on tens of thousands of healthy and cancerous kidney cells, a team from the Wellcome Trust Sanger Institute, the University of Cambridge, and other centers in the UK has tracked down transcriptomic similarities between Wilms tumor and developing kidney cells, as well as ties between adult kidney carcinoma and a rare kidney cell type.

As they reported online today in Science, the researchers compared available genome sequences for bulk tumor samples to single-cell RNA sequences for nearly 29,700 individual cells from kidney tumors and another 42,809 non-malignant cells from normal fetal, pediatric, or adult kidney and/or ureter tissue samples. Along with immune and non-immune cell clusters, the cells clustered into still other cell subtypes with shared transcriptomic features.

"Using large-scale single cell RNA sequencing, we could precisely define the characteristics of kidney tumor cells for the first time and compare them with healthy reference kidney cells from different development stages and ages," co-corresponding author Muzlifah Haniffa, a cellular medicine researcher at Newcastle University, said in a statement. "This approach will help towards understanding not only kidney cancer, but many other diseases that have their origin during development."

On the kidney cancer side, the single-cell transcriptomes represented tumor and immune cells from three individuals with Wilms tumor, three with clear cell renal cell carcinoma, and one with papillary renal cell carcinoma, the team noted. With the single-cell transcriptomes — and genotypes gleaned from the messenger RNA and genome sequence data — the group tracked down informative similarities between some of the cancerous and normal cell types.

In particular, the Wilms tumors cells showed transcriptome and genotype patterns that roughly lined up with those in fetal kidney cells, the researchers reported, particularly developing nephron cell subtypes such as ureteric bud cells and primitive vesicles. They tracked down similar cell signatures using bulk transcriptome data for another 124 Wilms tumor samples, but not in bulk gene expression profiles from normal adult kidney samples or other kidney tumor types.

"Wilms' tumor cells have the same characteristics of a normal developing kidney cell, which may have got 'stuck' during development," co-corresponding author Sam Behjati, a pediatrics researcher affiliated with the Sanger Institute, Cambridge University Hospitals, and the University of Cambridge, said in a statement. "This could lead to an entirely new model for treating childhood cancer, by manipulating the development state of the cells instead of trying to kill them with chemotherapy."

On the other hand, all but one of the adult renal cell carcinoma tumors shared transcriptomic features with a subtype of normal proximal convoluted tubular cells in the kidney. And the team saw markers from that cell type in bulk transcriptome data from the clear cell renal cell carcinoma and papillary renal cell carcinoma representatives in a set of more than 1,000 kidney cancers.

Among their subsequent analyses, the authors were also able to learn more about the microenvironment surrounding kidney tumors, uncovering signaling by cells with vascular endothelial growth factor activity and other normal cells lingering near tumors. The work "provides a scalable experimental strategy for determining the identity of human cancer cells," the authors wrote. 

And, more broadly, the results "make an important contribution towards the global Human Cell Atlas initiative that aims to map every cell in the human body and make this information available to researchers around the world," co-corresponding author Menna Clatworthy, a molecular biology researcher at the University of Cambridge, added in a statement.