| dc.description.abstract | A fundamental challenge when studying the evolution and origin of cancer is understanding the early events following oncogenic mutations. In the case of clear cell renal cell carcinoma (ccRCC), the truncal event is the inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. However, despite this event being near universal in all ccRCC cases, VHL inactivation alone does not lead to the formation of tumours, and the inactivation of a second tumour suppressor gene is needed for tumorigenesis. This raises important questions about how the concomitant loss of these tumour suppressors drives tumorigenesis and what early changes this loss imposes on cells.
To investigate these early events of ccRCC evolution, this study utilises a reporter mouse model that combines the inducible inactivation of Vhl with the expression of a tdTomato fluorescent marker in the renal tubular epithelium. This enables visualisation and extraction of Vhl-null cells from renal tissues before they undergo morphological alterations. This model was further expanded for the Polybromo-1 (Pbrm1) gene, the second most commonly mutated gene in ccRCC. By integrating histological assessments, molecular profiling, and digital pathology techniques, this study investigates time-dependent changes in survival, expansion, morphology, and clustering of renal tubular epithelial cells after Vhl and/or Pbrm1 inactivation. In addition, transcriptome analysis was carried out to elucidate the early changes imposed on cells after losing Vhl and Pbrm1.
The study revealed that while Pbrm1 inactivation does not significantly alter the expansion of Vhl-null cells within the kidney cortex, it plays a crucial role in driving early tumour-like morphological changes. Notably, the combined loss of Vhl and Pbrm1 results in the formation of dysplastic tumour-like lesions and cystic tubules, morphological alterations that do not appear when either gene is inactivated alone. Interestingly, despite thesemorphological shifts, transcriptome analyses showed that the impact of Pbrm1 inactivation on the gene expression profile of Vhl-null cells is relatively modest.
These results provide new perspectives on the early molecular and cellular changes that lead to ccRCC. They suggest that while Pbrm1 inactivation is necessary for initiating structural abnormalities in Vhl-null cells, its transcriptional effects are less pronounced than anticipated. This work highlights the need for further investigation into non-transcriptional mechanisms in ccRCC development and advances our understanding of the early stages of cancer evolution driven by Vhl and Pbrm1 mutations. | |
