{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:17:04Z","timestamp":1787912224941,"version":"build-2784847793"},"reference-count":60,"publisher":"Wiley","issue":"48","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871203"],"award-info":[{"award-number":["81871203"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hyperactivation of the PI3K\/AKT pathway is a hallmark of metastatic triple\u2010negative breast cancer (TNBC), but its drivers in TNBC\u00a0retaining wild\u2010type PTEN are poorly understood. Here, we identify Testis\u2010Specific Y\u2010Like Protein 5 (TSPYL5) \u2010the top metastasis\u2010associated gene from an unbiased bioinformatics screen\u2010 as a master regulator that resolves this paradox. Clinically,\n                    <jats:italic>TSPYL5<\/jats:italic>\n                    amplification and overexpression are robust predictors of metastatic progression and poor prognosis. High\u2010resolution single\u2010cell and spatial analyses reveal that\n                    <jats:italic>TSPYL5<\/jats:italic>\n                    defines a malignant subpopulation with stem\u2010like, genomically unstable, and pro\u2010metastatic properties. Functionally, TSPYL5 is sufficient to drive spontaneous polymetastasis from orthotopic tumors and is indispensable for post\u2010intravasation colonization, culminating in overt liver metastases in 60% of animals\u2014a phenotype absent in controls. Mechanistically, TSPYL5 sequesters the deubiquitinase USP10, thereby preventing it from stabilizing the tumor suppressor PTEN. This TSPYL5\u2010USP10 interaction triggers the proteasomal degradation of PTEN, circumventing its wild\u2010type status to hyperactivate PI3K\/AKT signaling and unleash a ZEB1\u2010driven metastatic program. This study delineates a complete TSPYL5\u2010USP10\u2010PTEN axis, providing a new paradigm for the post\u2010translational tumor suppressor inactivation in TNBC. Our work validates TSPYL5 as a biomarker for PI3K pathway dependency and establishes the TSPYL5\u2010USP10 interface as a tractable therapeutic target to restore PTEN function and combat metastatic TNBC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520273","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T15:20:38Z","timestamp":1780586438000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TSPYL5 Promotes Triple\u2010Negative Breast Cancer Metastasis by Antagonizing USP10\u2010Mediated PTEN Stabilization to Unleash a ZEB1\u2010Dependent EMT Program"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiaying","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Medical Genetics State Key Laboratory of Biotherapy West China Hospital, Sichuan University  Chengdu China"},{"name":"Department of Rehabilitation Medicine Xuanwu Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics State Key Laboratory of Biotherapy West China Hospital, Sichuan University  Chengdu China"},{"name":"Frontiers Science Center for Disease\u2010related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics State Key Laboratory of Biotherapy West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaokun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics State Key Laboratory of Biotherapy West China Hospital, Sichuan University  Chengdu 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