Cellular mRNA signals in human kidney tumors

Tumor cells may produce many of the same messenger RNAs (mRNA) as the cell they derive from. The relative abundance of these mRNAs, the transcriptiomic profile, may provide clues into the origin and development of tumors. Here we investigated the cellular origins of 1,300 childhood and adult renal tumors, spanning 7 different subtypes. We decomposed tumor bulk transcriptomes into single cell components, measuring the abundance of single cell derived reference “cellular signals” in each tumor. We quantified the extent to which each tumor utilized fetal cellular signals, finding that all childhood renal tumors are definitively fetal. This replaces the long-held presumption of “fetalness” with a precise, quantitative readout of immaturity. Analyzing cellular signals in each tumor type, we recapitulated previous findings for some, whilst providing novel insights into other, less well understood tumor types. For example, our analyses predicted fetal interstitial cells as the cell of origin of the infant kidney tumor, congenital mesoblastic nephroma, and demonstrate that another childhood kidney cancer, malignant rhabdoid tumor, arises from mesodermally derived cells in early development. We found remarkable uniformity in the cell signal of each tumor type, indicating the possible therapeutic and diagnostic utility of cellular signal decomposition. We demonstrated this utility with an example of a child with a cryptic renal tumor, which had not been identifiable by conventional diagnostic work-up but was clearly classified with our approach. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.