Integrated single-cell, genomic, and clinical analyses enabled a preclinically validated strategy to prevent or treat kidney cancer

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 could 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 cancer initiation and progression and revealed: the hyperactivated YAP1, via manipulating multiple signaling pathways, induced epithelial cell transformation, MDSC (Myeloid-derived suppressor cells) accumulation, and pRCC development. Depletion of MDSC blocked YAP1-induced kidney overgrowth and tumorigenesis. Inhibiting YAP1 activity with MGH-CP1, a newly developed TEAD inhibitor, blocked MDSC accumulation and suppressed tumor development.

Sep 3, 2023 1:00 PM — 3:00 PM