{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:07:10Z","timestamp":1779944830243,"version":"3.53.1"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bladder cancer (BLCA) remains a major cause of cancer-related mortality, particularly in advanced and metastatic stages. Identifying molecular drivers of tumor aggressiveness is critical for developing targeted therapies. Adhesion G protein\u2013coupled receptor D1 (ADGRD1, also known as GPR133) is an orphan aGPCR recently implicated in tumorigenesis. However, its role in bladder cancer and underlying signaling mechanisms remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The clinical significance of ADGRD1 was analyzed using GEPIA3 datasets, focusing on clinical stage and prognosis. Stable ADGRD1-knockdown and overexpression BLCA cell lines were established. qPCR, Western blot, CCK-8, colony formation, wound-healing, Transwell, and HUVEC tube formation assays were used to assess proliferation, migration, invasion, and angiogenesis. Xenograft models were used to evaluate\n                      <jats:italic>in vivo<\/jats:italic>\n                      tumor growth. PI3K\/AKT\/mTOR pathway activity was examined by Western blot, and its function validated using SC79 (AKT activator) and LY294002 (PI3K inhibitor).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ADGRD1 expression was significantly enriched in advanced-stage and high-grade BLCA, where it serves as a robust predictor of poor overall survival and progression-free interval. Functional assays demonstrated that ADGRD1 promotes BLCA cell proliferation, migration, invasion, and endothelial tube formation\n                      <jats:italic>in vitro<\/jats:italic>\n                      , and enhances tumor growth and angiogenesis\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Importantly, ADGRD1-high cells enhanced endothelial tube formation by upregulating a secretome rich in VEGF, PDGF, and IL-8. Mechanistically, ADGRD1 activated the PI3K\/AKT\/mTOR signaling cascade, as evidenced by increased phosphorylation of pathway components. Pharmacological inhibition of PI3K\/AKT\/mTOR reversed the oncogenic and pro-angiogenic effects of ADGRD1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identifies ADGRD1 as a key progression-associated driver in BLCA. By modulating the PI3K\/AKT\/mTOR signaling axis and the pro-angiogenic microenvironment, ADGRD1 facilitates tumor growth and neovascularization. ADGRD1 may serve as a promising prognostic biomarker and therapeutic target for advanced BLCA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1817872","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:51:21Z","timestamp":1779943881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ADGRD1 promotes bladder cancer progression and angiogenesis via the PI3K\/AKT\/mTOR-mediated pro-angiogenic secretome"],"prefix":"10.3389","volume":"16","author":[{"given":"Chen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Hebei North University","place":["Zhangjiakou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, Hebei North College","place":["Zhangjiakou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Hebei North College","place":["Zhangjiakou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Hebei North University","place":["Zhangjiakou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Hebei North University","place":["Zhangjiakou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41572-023-00468-9","article-title":"Bladder cancer","volume":"9","author":"Dyrskj\u00f8t","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2023.03.029","article-title":"Epidemiology of bladder cancer in 2023: A systematic review of risk factors","volume":"84","author":"Jubber","year":"2023","journal-title":"Eur Urol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-076743","article-title":"Advances in diagnosis and treatment of bladder cancer","volume":"384","author":"Lopez-Beltran","year":"2024","journal-title":"BMJ"},{"key":"B4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.semcancer.2021.06.019","article-title":"Attacking the PI3K\/Akt\/mTOR signaling pathway for targeted therapeutic treatment in human cancer","volume":"85","author":"Yu","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7234-0_23","article-title":"Targeting the PI3K\/AKT\/mTOR pathway in bladder cancer","volume":"1655","author":"Sathe","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1021\/acsptsci.9b00093","article-title":"The emerging role of adhesion GPCRs in cancer","volume":"3","author":"Gad","year":"2020","journal-title":"ACS Pharmacol Transl Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-41523-9_17","article-title":"Adhesion GPCRs in tumorigenesis","volume":"234","author":"Aust","year":"2016","journal-title":"Handb Exp Pharmacol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2024.10.022","article-title":"Targeting adhesion G protein-coupled receptors. 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