{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T09:06:46Z","timestamp":1789722406576,"version":"4.0.1"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is an age-associated malignancy closely linked to the extracellular matrix (ECM). However, the impact of age-related ECM changes in the normal pancreas on PDAC progression remains unclear. Here, we find that increased linear ECM alignment in normal pancreatic tissues from aged PDAC patients is associated with PDAC progression and worse outcomes. Furthermore, serum methylmalonic acid (MMA) levels are elevated in aged PDAC patients and associated with increased linear ECM alignment in normal pancreatic tissues of PDAC patients. Functionally, MMA promotes LOXL2 expression in pancreatic stellate cells (PSCs), increases linear ECM alignment in normal pancreatic tissues, and facilitates tumor progression. Mechanistically, MMA upregulates KLF10, which forms a transcriptional complex with SP1 to enhance LOXL2 expression in PSCs. Our study demonstrates the role of MMA-induced LOXL2<jats:sup>+<\/jats:sup>PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients.<\/jats:p>","DOI":"10.1038\/s41419-025-07751-5","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T18:47:01Z","timestamp":1748371621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MMA-induced LOXL2+ PSCs promote linear ECM alignment in the aging pancreas leading to pancreatic cancer progression"],"prefix":"10.1038","volume":"16","author":[{"given":"Wenyuan","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haodong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeqian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-4549","authenticated-orcid":false,"given":"Shan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7664-7148","authenticated-orcid":false,"given":"Jiahua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"7751_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","volume":"72","author":"RL Siegel","year":"2022","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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Collagen fibril network and elastic system remodeling in a reconstructed skin transplanted on nude mice. Matrix Biol. 2001;20:463\u201373.","journal-title":"Matrix Biol"},{"key":"7751_CR7","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1158\/2159-8290.CD-18-0168","volume":"9","author":"BL Ecker","year":"2019","unstructured":"Ecker BL, Kaur A, Douglass SM, Webster MR, Almeida FV, Marino GE, et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 2019;9:82\u201395.","journal-title":"Cancer Discov"},{"key":"7751_CR8","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1158\/2159-8290.CD-18-0193","volume":"9","author":"A Kaur","year":"2019","unstructured":"Kaur A, Ecker BL, Douglass SM, Kugel CH 3rd, Webster MR, et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. 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Animal experiments were conducted according to guidelines approved by the Institutional Animal Care and Use Committee of Southeast University. All animal experiments were approved by the Institutional Animal Care and Use Committee of Southeast University (20230306002).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"419"}}