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While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. <jats:italic>DUSP6<\/jats:italic> is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High <jats:italic>DUSP6<\/jats:italic> expression correlates with the quasi-mesenchymal\/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked <jats:italic>DUSP6<\/jats:italic> to pathways involved in cell migration and metabolism in metastatic samples. Functionally, <jats:italic>DUSP6<\/jats:italic> knockdown in PDAC cells increases ERK\/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and <jats:italic>DUSP6<\/jats:italic> knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression.<\/jats:p>","DOI":"10.1038\/s41598-025-12967-8","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:24:34Z","timestamp":1759242274000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells"],"prefix":"10.1038","volume":"15","author":[{"given":"Mariana T.","family":"Ruckert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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Proceedings of the National Academy of Sciences of the United States of America 102(43) (2005).","DOI":"10.1073\/pnas.0506580102"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12967-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12967-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12967-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:24:44Z","timestamp":1759242284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12967-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["12967"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-12967-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"24 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"In the past three years, CAL has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05\/07\/2015; US Patent No: 20190136238, 05\/09\/2019; International Patent No: WO2013177426-A2, 04\/23\/2015). All the remaining authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Experiments involving mice were approved by the Ethics Committee on Animal Research at Ribeirao Preto Medical School, University of S\u00e3o Paulo (protocol# 016\/2018), and conducted in accordance with the Guidelines of the Brazilian College of Animal Experimentation. Experiments performed at the Massachusetts General Hospital and the University of Kansas Medical Center were subjected to IACUC protocols (2005N000148 and 2019N000116; and 22-02-226, respectively) and were conducted according to the ARRIVE guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"This study was supported by S\u00e3o Paulo Research Foundation (FAPESP 2015\/10694-5) granted to VSS. MTR was supported by CAPES Foundation (Finance Code 001) and Fulbright Association. JS is supported in part by the National Cancer Institute of the National Institutes of Health under award number R37CA262209. MVS received funds from the University of Kansas Cancer Center. CAL was supported by the NCI (R37CA237421, R01CA248160, and R01CA244931).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Financial support"}}],"article-number":"33996"}}