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

Publication Title

JCI Insight

Authors

• Jianguo Huang, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Xingliang Liu, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Warren Floyd
• William Haugh, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Zhaoyu Sun, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Melissa Kasiewicz, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Yaping Wu, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Brian D. Piening, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• John Welle, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Wesley K Rosales, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Venkatesh Rajamanickam, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• So Young Kim
• Eric S Xu
• Lixia Luo
• Yan Ma
• Rutulkumar Patel
• Ziqiang Zhang
• Brady Bernard, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• William L. Redmond, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• Walter Urba, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• R Bryan Bell, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.Follow
• David G Kirsch

Document Type

Article

Publication Date

8-24-2026

Keywords

Animals; Tumor Suppressor Proteins; Mice; Ubiquitin Thiolesterase; Humans; Sarcoma; Polo-Like Kinase 1; Proto-Oncogene Proteins; Protein Serine-Threonine Kinases; Cell Cycle Proteins; CRISPR-Cas Systems; Cell Line, Tumor; Tumor Microenvironment; Female; Disease Models, Animal; Cancer; Genetics; Mouse models; Oncology; Therapeutics.; oregon; chiles

Abstract

Undifferentiated pleomorphic sarcoma (UPS) is one of the most common adult soft-tissue sarcomas (STSs), yet therapeutic progress remains limited because of 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 STSs.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology

Specialty/Research Institute

Pharmacy

DOI

10.1172/jci.insight.192686