A tailored in vivo CRISPR screen identifies <i>BAP1</i> as a potent tumor suppressor of sarcoma

Jianguo Huang; Xingliang Liu; Warren Floyd; William Haugh; Zhaoyu Sun; Melissa J. Kasiewicz; Yaping Wu; Brian Piening; John T. Welle; Wesley K. Rosales; Venkatesh Rajamanickam; So Young Kim; Eric S. Xu; Lixia Luo; Yan Ma; Rutulkumar Patel; Ziqiang Zhang; Brady Bernard; William L. Redmond; Walter J. Urba; R. Bryan Bell; David G. Kirsch

doi:10.1172/jci.insight.192686

¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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¹Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, United States of America

²Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

³Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America

⁴Department of Radiation Oncology, Duke Univeristy Medical Center, Durham, United States of America

⁵Department of Respiratory and Critical Care Medicine, Fudan University Pudong Medical Center, Shanghai, China

⁶Department of Radiation Oncology, University of Toronto, Toronto, Canada

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JCI Insight. https://doi.org/10.1172/jci.insight.192686.
Copyright © 2026, Huang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 30, 2026 - Version history

Undifferentiated pleomorphic sarcoma (UPS) is one of the most common adult soft tissue sarcomas (STS), yet therapeutic progress remains limited due to the absence of recurrent oncogenic driver mutations. To identify tumor suppressors contributing to UPS pathogenesis, we performed a customized in vivo CRISPR/Cas9 screen in mice. This approach identified BRCA1-associated protein 1 (BAP1) as a potent tumor suppressor in STS. Integrative analyses using RNA sequencing, multiplex immunohistochemistry, and flow cytometry revealed that Bap1-deficient sarcomas exhibited a markedly immunosuppressive tumor microenvironment. Consistent with these findings, BAP1 protein expression was reduced in human UPS, whereas polo-like kinase 1 (PLK1) expression was elevated. Functional studies demonstrated that PLK1 was required for the growth and survival of Bap1-deficient sarcomas. Pharmacologic inhibition of PLK1 with volasertib significantly suppressed tumor growth in both syngeneic and autochthonous mouse models. Moreover, combining PLK1 inhibition with anti-PD-1 therapy enhanced tumor control and improved survival compared with either treatment alone. Together, these results identify PLK1 as a potential therapeutic vulnerability in BAP1-deficient sarcomas and support further evaluation of combined PLK1 inhibition and immune checkpoint blockade as a treatment strategy for a subset of STS.

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A tailored in vivo CRISPR screen identifies BAP1 as a potent tumor suppressor of sarcoma

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