Defining how early molecular events in carcinogenesis—like the activation of an oncogene or the loss of a tumor suppressor—shape the cellular responses and later characteristics of tumors has proved challenging. Researchers led by Ludwig Oxford’s Samvid Kurlekar, Joanna Lima and Peter Ratcliffe reported in a March Cancer Research paper their development of an experimental platform to address this challenge. They applied their method to examine the longitudinal changes induced by the loss of the tumor suppressor, VHL, which drives the kidney cancer clear cell renal cell carcinoma. The loss of VHL expression in their system was linked to the expression of a genetic reporter, tdTomato, permitting the researchers to isolate and analyze cells of interest over time via microscopic and single-cell RNA analysis. Their analysis uncovered distinct responses to loss of the Vhl protein in different cell types. The study also defined a proximal tubular cell class with oncogenic potential and revealed long-term adaptive changes in areas of the renal epithelium caused by the disruption of Vhl activity. Aside from its presentation of a new system for tracking how early oncogenic events alter cancer initiation and progression, the study offered specific insights into how Vhl suppresses tumorigenesis and how its loss drives the evolution of this kidney cancer.
Oncogenic cell tagging and single-cell transcriptomics reveal cell type-specific and time-resolved responses to Vhl inactivation in the kidney
Cancer Research, 2024 March 19