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PIK3CA, which encodes the catalytic p110\u03b1 subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR\/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K\/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3K\u03b1 inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-03058-w","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T08:36:50Z","timestamp":1784018210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression"],"prefix":"10.1186","volume":"24","author":[{"given":"Karthik Reddy","family":"Kami Reddy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasanta","family":"Putluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danthasinghe Waduge Badrajee","family":"Piyarathna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hyoung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaditya Krishna","family":"Arun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin B","family":"Jorvekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchao","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Khurshidul","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra Sekhar","family":"Amara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abu Hena Mostafa","family":"Kamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra Shekar R.","family":"Ambati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kraushaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana Langer","family":"Gramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison C","family":"Bellman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leomar Y","family":"Ballester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Taylor","family":"Ripley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth P","family":"Lerner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni J","family":"Bollag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha K","family":"Terris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong-Xian","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benny Abraham","family":"Kaipparettu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Lotan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagireddy","family":"Putluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"3058_CR1","doi-asserted-by":"crossref","unstructured":"Zhang Y, Rumgay H, Li M, Yu H, Pan H, Ni J. 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PMC10867091 for service on a Scientific Advisory Board for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies; non-branded educational programs supported by Exelixis and Pfizer; and research funding for clinical trials from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and The University of Texas MD Anderson Cancer Center. M.J.E. reports grants from CPRIT and McNair Medical Foundation during the conduct of the study; personal fees from AstraZeneca outside the submitted work; in addition, M.J.E. has a patent for PAM50 issued, licensed, and with royalties paid from Veracyte. M.J.E. is current employee of AstraZeneca. H.C.H. is a consultant for Avenge Bio, Inc. A.S.K. is Scientific Advisor to Karkinos Health Care Pvt Ltd, India and unpaid visiting faculty to Sri Sathya Sai Institute for Higher Learning, India. 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Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs. Signal Transduct Target Ther. 2025;10(1):92. PMC11926384 Oncology, Daiichi-Sankyo, AstraZeneca, Molecular Health, and Merck, all outside the submitted work. C.D. is cofounder of Sividon Diagnostics. In addition, C.D. has a patent on VMScope digital pathology software with royalties paid; a patent WO2020109570A1-cancer immunotherapy pending; and patents WO2015114146A1 and WO2010076322A1-therapy response issued. P.J. reports research grants and travel expenses from GILEAD Sciences GmbH outside the submitted work. N.H. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH reports financial funding from AstraZeneca and Myriad during the conduct of the study; received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Stemline Menarini, Celgene\/BMS, Novartis, Pfizer and Roche (paid to the institution); GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. S.L. declares to be the CEO of the GBG Forschungs GmbH. GBG Forschungs GmbH receives grants and other from Abbvie, grants from AstraZeneca, grant from Amgen, grants from DSI, grants from Gilead, Grants from Molecular Health, grants from Celgene\/BMS, grants from Novartis, grants from Pfizer, grants from Roche, grant from Stemline\/Menarini, financial support from Astra Zeneca, Gilead, Myriad, Novartis, Pfizer, BMS, Sanofi, Lilly, MSD; Consulting fees from following: AstraZeneca, Abbvie, Amgen, Cellcuity, DSI, Gilead, Novartis, Incyte, Pfizer, BMC, Sanofi, Lilly, MSD, Esai, Exact Science, Relay, Stemline, GSK, BioNtech, Olema, Roche; Payment Honoria: AZ, Amgen, Agendia, DSI, Gilead, Novartis, Pfizer, BMS, Stemline\/Menarini, Lilly, MSD, Seagen, Medscape, Pierre Fabre, Roche; Travel support from: DSI, ESMO, SCGCC. S.L. reports leadership in: ESMO, SBGCC, SABCS, and Kommission Mamma AGO, S.L. reports receipt of drug equipment in trials from: Gilead, AZ, Celgene\/BMS, Novartis, Pfizer, and Roche. GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. The other authors declare no conflicts of interest. Ethics approval and consent to participate: Immunohistochemical staining and evaluation of breast cancer patient samples was approved by the Ethics Committee of the University of Marburg (Ethics Opinion No 38\/20). All xenograft experiments were performed according to the German animal welfare law and the European legislation for the protection of animals used for scientific purposes (2010\/63\/EU) and were approved by the regional board (RP Giessen)."},{"issue":"2","key":"3058_CR45","doi-asserted-by":"publisher","first-page":"pkz019PMC648968","DOI":"10.1093\/jncics\/pkz019","volume":"3","author":"JH Gohlke","year":"2019","unstructured":"Gohlke JH, Lloyd SM, Basu S, et al. Methionine-Homocysteine Pathway in African-American Prostate Cancer. JNCI Cancer Spectr. 2019;3(2):pkz019PMC6489686.","journal-title":"JNCI Cancer Spectr"},{"issue":"6","key":"3058_CR46","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1016\/j.juro.2016.01.039","volume":"195","author":"FC von Rundstedt","year":"2016","unstructured":"von Rundstedt FC, Rajapakshe K, Ma J, et al. Integrative pathway analysis of metabolic signature in bladder cancer: a linkage to the cancer genome atlas project and prediction of survival. J Urol. 2016;195(6):1911\u20139.","journal-title":"J Urol"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-026-03058-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-026-03058-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-026-03058-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:03:04Z","timestamp":1792422184000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-026-03058-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3058"],"URL":"https:\/\/doi.org\/10.1186\/s12964-026-03058-w","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]},"assertion":[{"value":"30 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All human deidentified samples were obtained under the H-35808 protocol approved by institutional review board (IRB). All animal studies were approved by Baylor College of Medicine under protocol number AN-7324 in accordance with IACUC guidelines. For the study, all the experiments were performed according to the protocol approved by the Institutional Biological & Chemical (IBC) Safety Committee, BCM under the protocol number D-499.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"562"}}