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Hyperactivated YAP1 is essential for sustainable progression of renal clear cell carcinoma

Oncogene volume 44, pages 2142–2157 (2025)Cite this article

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Abstract

The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.

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Fig. 1: YAP1 activation is associated with ccRCC progression.
Fig. 2: YAP1 stimulates the proliferation of renal carcinoma cells in vitro and in vivo.
Fig. 3: Enrichment of the genes and pathways involved in angiogenesis during YAP1-induced ccRCC progression.
Fig. 4: YAP1 and FGF form a feed-forward loop to drive the proliferation of renal cancer cells.
Fig. 5: YAP1 is required for basal and FGF-mediated endothelial cell proliferation and function.
Fig. 6: YAP1 is essential for VEGF-induced proliferation of kidney tumor-associated endothelial cells.
Fig. 7: Targeting the dual role of YAP1 inhibits kidney tumor growth in xenograft mouse models.
Fig. 8: A schematic diagram showing mechanisms by which YAP promotes ccRCC development.

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Data availability

The raw and processed RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession number/code GSE290118. Other data supporting the findings of this study are available within the article and its supplementary information files.

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Acknowledgements

This work was partially supported by the National Cancer Institute/National Institute of Health (1R01CA197976, 1R01CA201500, and 5R01CA279385), University of Nebraska Medical Center Graduate student Fellowship, the Olson Center for Women’s Health (no number), The Fred & Pamela Buffett Cancer Center (Lb595), the Colleen’s Dream Foundation (no number), the Ruggles Family Foundation, VA Senior Research Career Scientist Award, IK6 BX005797, and the Vincent Memorial Hospital Foundation/Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital (No number).

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  1. These authors contributed equally: Xiangmin Lv, Jiyuan Liu, Kazi Islam, Jinpeng Ruan.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Xiangmin Lv, Jiyuan Liu, Kazi Islam, Jinpeng Ruan, Chunbo He, Peichao Chen, Cong Huang, Hongbo Wang, Anjali Dhar, Madelyn Moness, Davie Shi, Savannah Murphy, Xingeng Zhao, Siyi Yang, Isabelle Montoute, Aneeta Polakkattil, Andie Chung, Emily Ruiz, Brianna Carbajal, Alekhya Padavala, Li Chen & Cheng Wang

  2. Department of Obstetrics and Gynecology, Olson Center for Women’s Health, University of Nebraska Medical Center, Omaha, NE, USA

    Chunbo He, Guohua Hua & John S. Davis

  3. Department of Chemistry, Dartmouth College, Hanover, NH, USA

    Anjali Dhar

  4. Department of Neurobiology, Northwestern University, Evanston, IL, USA

    Davie Shi

  5. Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA

    Isabelle Montoute

  6. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA

    Emily Ruiz

  7. Department of Stem cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    Brianna Carbajal

  8. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Xingcheng Chen & John S. Davis

  9. Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    John S. Davis

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XL contributed to the conceptualization, experimental design and performance, data analysis, and manuscript preparation; JL contributed to RNA-seq, sequencing data analysis, and manuscript preparation; JR and KI contributed to cell culture, western blotting, tube formation, immunohistochemical analyses, and manuscript review; CH (Chunbo He) and GH, and C.H. (Cong Huang) contributed to viral package, 3D culture, tube formation assay, animal model development, and manuscript review. PC, HW, AD, XZ, DS, MM, SM, IM, ER., BC, LC, XC conducted real-time PCR and histological analyses and reviewed the manuscript. SY contributed to bioinformatics analysis; JSD contributed to data interpretation and manuscript review; CW supervised these studies and contributed to the conceptualization, experimental design, data analysis/interpretation, and manuscript preparation.

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Correspondence to Cheng Wang.

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The authors declare no competing interests.

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Xenograft tumor mouse models were generated and used to examine the role of hyperactivated YAP1 oncoprotein in ccRCC progression. Mouse handling and all experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Nebraska Medical Center (UNMC) and Massachusetts General Hospital (MGH). No human subjects were involved in this study.

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Lv, X., Liu, J., Islam, K. et al. Hyperactivated YAP1 is essential for sustainable progression of renal clear cell carcinoma. Oncogene 44, 2142–2157 (2025). https://doi.org/10.1038/s41388-025-03354-8

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  • DOI: https://doi.org/10.1038/s41388-025-03354-8

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