Gene expression profile at single cell level of kidney cells of papillary renal cell carcinoma from mice at different stages
The role of the Hippo/YAP signaling pathway in renal cell carcinoma remains unclear. Large-scale cancer genetic/genomic studies demonstrated that papillary renal cell carcinoma (PRCC) is featured with a frequent shallow deletion of the upstream tumor suppressors of the Hippo/YAP signaling pathway, suggesting that this signaling pathway may play a role in PRCC development. We developed a transgenic mouse model with a renal epithelial cell-specific hyperactivation of YAP1 and found that hyperactivation of YAP1 can induce dedifferentiation and transformation of renal tubular epithelial cells leading to the development of PRCC. We analyzed at the single-cell resolution the cellular landscape alterations during PRCC development. Our data indicated that the hyperactivated YAP1, via manipulating multiple signaling pathways, induced epithelial cell transformation, MDSC accumulation, and PRCC development. Blocking YAP1 activity with MGH-CP1, a newly developed TEAD inhibitor, suppressed tumor development and MDSC accumulation. Our results identify the disrupted Hippo/YAP signaling as a major contributor to PRCC and suggest that targeting the disrupted Hippo pathway represents a novel strategy to prevent and treat PRCC. Overall design: Kidneys from Pax8-rtTA;tet-on-YAPS127A mice (Pax8-YAPS127A) treated with doxycycline (Dox) for 0, 7days and 4 months.