Tracing Renal Cell Carcinomas back to the Nephron

Recent advances using large-scale genomics have detailed subtype-specific RCC anomalies that have provided valuable clues into what specific genetic insults drive renal tumorigenesis and into the temporal order in which these events occur. Detailed descriptions of the cell types that constitute the normal nephron and their response to physiological insults have yielded insights into the cellular origin(s) of renal tumors. A new generation of mouse models of clear cell RCC, incorporating multiple genetic alterations observed in human disease, are providing vital information on RCC biology and represent an added venue for answering therapy-related questions. Renal cell carcinomas (RCCs) are a heterogeneous group of tumors derived from the epithelial cells of the nephron. In recent years the genetic landscape of these tumors has been detailed, leading to progress in mouse modeling of the human disease. In parallel, substantial advancements have been made in describing the transcriptional programs of normal nephron cell types and how they respond to renal insults. Integrating these research fields may provide a deeper understanding of renal tumor initiation and progression, and provide leads that can be conveyed into mouse models that faithfully recapitulate the different RCC subtypes. We summarize here the genetic lesions and molecular pathways that define RCC subtypes and discuss how these relate to cell-of-origin and renal repair programs. Renal cell carcinomas (RCCs) are a heterogeneous group of tumors derived from the epithelial cells of the nephron. In recent years the genetic landscape of these tumors has been detailed, leading to progress in mouse modeling of the human disease. In parallel, substantial advancements have been made in describing the transcriptional programs of normal nephron cell types and how they respond to renal insults. Integrating these research fields may provide a deeper understanding of renal tumor initiation and progression, and provide leads that can be conveyed into mouse models that faithfully recapitulate the different RCC subtypes. We summarize here the genetic lesions and molecular pathways that define RCC subtypes and discuss how these relate to cell-of-origin and renal repair programs.