Targeting the disrupted Hippo signaling to prevent neoplastic renal epithelial cell immune evasion

Xiangmin Lv, Jiyuan Liu, Jinpeng Ruan, Peichao Chen, Chunbo He, Xingeng Zhao, Cong Huang, Li Chen, Hongbo Wang, Guohua Hua, Davie Shi, Siyi Yang, Madelyn L. Moness, Isabelle Montoute, Anjali Dhar, Xingcheng Chen, Raj Kumar, Hu Lu, Ruslan Sadreyev, Oladapo Yeku, Xu Wu, John S. Davis and Cheng Wang ()
Additional contact information
Xiangmin Lv: Harvard Medical School
Jiyuan Liu: Harvard Medical School
Jinpeng Ruan: Harvard Medical School
Peichao Chen: Harvard Medical School
Chunbo He: Harvard Medical School
Xingeng Zhao: Harvard Medical School
Cong Huang: Harvard Medical School
Li Chen: Harvard Medical School
Hongbo Wang: Harvard Medical School
Guohua Hua: University of Nebraska Medical Center
Davie Shi: Harvard Medical School
Siyi Yang: Harvard Medical School
Madelyn L. Moness: Harvard Medical School
Isabelle Montoute: Harvard Medical School
Anjali Dhar: Harvard Medical School
Xingcheng Chen: University of Nebraska Medical Center
Raj Kumar: Harvard Medical School
Hu Lu: Harvard Medical School
Ruslan Sadreyev: Harvard Medical School
Oladapo Yeku: Harvard Medical School
Xu Wu: Harvard Medical School
John S. Davis: University of Nebraska Medical Center
Cheng Wang: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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. Here we develop a transgenic mouse model with a renal epithelial cell-specific hyperactivation of YAP1 and find that hyperactivation of YAP1 can induce dedifferentiation and transformation of renal tubular epithelial cells leading to the development of pRCC. We analyze at the single-cell resolution the cellular landscape alterations during cancer initiation and progression. Our data indicate that the hyperactivated YAP1, via manipulating multiple signaling pathways, induces epithelial cell transformation, MDSC (Myeloid-derived suppressor cells) accumulation, and pRCC development. Interestingly, we find that depletion of MDSC blocks YAP1-induced kidney overgrowth and tumorigenesis. Inhibiting YAP1 activity with MGH-CP1, a recently developed TEAD inhibitor, impedes MDSC accumulation and suppresses tumor development. Our results identify the disrupted Hippo/YAP signaling as a major contributor to pRCC and suggest that targeting the disrupted Hippo pathway represents a plausible strategy to prevent and treat pRCC.

Date: 2025
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DOI: 10.1038/s41467-025-57697-7

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