{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:25:08Z","timestamp":1787163908415,"version":"build-2736575974"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"National Science and Technology Council","award":["113-2314-B-038-068"],"award-info":[{"award-number":["113-2314-B-038-068"]}]},{"DOI":"10.13039\/100020595","name":"NSTC","doi-asserted-by":"publisher","award":["113-2314-B-038-150"],"award-info":[{"award-number":["113-2314-B-038-150"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"name":"TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center"},{"name":"Higher Education Sprout"},{"name":"Ministry of Education"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite breakthroughs in molecularly targeted and immune therapies, the prognosis for patients with urinary bladder cancer (UBC) has remained unsatisfactory over the past few decades. Understanding the molecular underpinnings of UBC treatment refractoriness is crucial for identifying novel therapeutic targets and strategies. Cancer stemness plays a pivotal role in the oncogenesis and treatment resistance of UBC, while the underlying molecular regulatory mechanisms are poorly understood. We identified isoform 1 of ASPM (ASPM-i1) as the most upregulated stemness-associated factor in tumorigenic UBC cells, predominantly expressed by ALDH1+ stem-like cancer cells. Pairing genetic ASPM-i1 inhibition with standard chemotherapeutic agents used in the treatment of UBC, including cisplatin and gemcitabine, circumvents the treatment resistance of tumorigenic and stem-like UBC cells. Mechanistically, ASPM-i1 interacts with the Disheveled (DVL) and intracellular NOTCH proteins, thereby attenuating CUL3- or FBXW7-mediated ubiquitination and the subsequent proteasomal degradation. The regulatory module concomitantly enhances the activities and ligand responsiveness of the Wnt and Notch signaling pathways in UBC cells. As a result, ASPM-i1 inhibition sensitized tumorigenic UBC cells to chemotherapy in a NOTCH- and DVL-dependent manner. In human UBC tissues, ASPM-i1 shows substantial cell-to-cell heterogeneity and is upregulated in a subset (46.4%) of tumors, correlating with poor clinical prognosis. This study reveals a crucial co-regulatory module of Notch and Wnt signaling that mediates stemness and chemotherapy resistance in tumorigenic UBC cells; its inhibition provides a novel approach to enhance chemosensitivity and improve therapeutic outcomes in human UBC.<\/jats:p>","DOI":"10.1093\/stmcls\/sxag002","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T12:42:05Z","timestamp":1767876125000},"source":"Crossref","is-referenced-by-count":1,"title":["Chemotherapy resistance of urinary bladder cancer mediated by a Notch and Wnt co-regulatory module of stemness"],"prefix":"10.1093","volume":"44","author":[{"given":"Li-Hsin","family":"Cheng","sequence":"first","affiliation":[{"name":"Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]},{"name":"TMU Core Laboratory of Organoids Technology (TCLOT), Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Wei","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University , Tainan City, 704302,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-2518","authenticated-orcid":false,"given":"Pei-Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University , 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Yan","family":"Liao","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]},{"name":"TMU Core Laboratory of Organoids Technology (TCLOT), Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Chen","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Taipei Veterans General Hospital , Taipei City, 112201,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Chi","family":"Hsu","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, I-Shou University , Kaohsiung City, 824410,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Chou","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1612-2868","authenticated-orcid":false,"given":"Kelvin K","family":"Tsai","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]},{"name":"TMU Core Laboratory of Organoids Technology (TCLOT), Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]},{"name":"Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University , Taipei City, 116079,","place":["Taiwan"]},{"name":"TMU Research Center of Cancer Translational Medicine, Taipei Medical University , Taipei City, 110301,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"2026040200053606400_sxag002-B1","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J 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