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This study aimed to investigate how the effect of chemotherapy on the primary tumor shapes the hepatic pre-metastatic niches (PMNs), which remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RNA sequencing was performed in a PDAC cohort to identify transcriptomic features associated with metastasis. We employed orthotopic and liver metastatic tumor models in mice to investigate the effects of extracellular vesicles derived from chemotherapy-treated PDAC cells, referred to as senescence-associated extracellular vesicles (S-EVs), on the hepatic PMNs. Mechanistically, we integrated proteomics and metabolomics to elucidate the molecular mechanisms by which S-EVs mediate hepatic metabolic reprogramming. Further, we utilized hepatocyte-specific Ache-knockout mice to validate the molecular mechanisms through which S-EVs promote liver metastasis in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chemotherapy-induced senescence in primary tumors correlated with PDAC liver metastasis and poor prognosis. S-EVs facilitated PMNs formation by promoting hepatic phosphatidylcholine (PC) accumulation. Mechanistically, S-EV-delivered hnRNPA1 stabilized AChE mRNA, thereby driving PC accumulation in the liver. In vitro co-culture system, PC depletion in hepatocytes successfully restored the impaired cytotoxicity of CD8\u207a T cells caused by S-EVs. Consistently, hepatocyte-specific Ache ablation in vivo restored S-EV-impaired CD8\u207a T cells cytotoxicity. Inhibition of AChE with pyridostigmine remodeled the hepatic PMNs and suppressed liver metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>S-EVs from chemotherapy-induced senescent PDAC cells reshaped hepatic PMNs through AChE-dependent PC accumulation, thereby impairing CD8\u207a T cell cytotoxicity and promoting PDAC liver metastasis. Targeting AChE with pyridostigmine represented a promising strategy to prevent metastasis and augment the therapeutic efficacy of NAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03741-3","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T14:46:42Z","timestamp":1779461202000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extracellular vesicles from chemotherapy-induced senescent tumor cells reprogram hepatic phospholipid metabolism to promote pancreatic cancer liver metastasis"],"prefix":"10.1186","volume":"45","author":[{"given":"Bai\u2019an","family":"Tao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yecheng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenteng","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenmei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deliang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"3741_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41421-021-00366-y","volume":"8","author":"X Fan","year":"2022","unstructured":"Fan X, Lu P, Wang H, Bian S, Wu X, Zhang Y, et al. 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Cell Rep. 2023;42:113401.","journal-title":"Cell Rep"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-026-03741-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03741-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03741-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:03:13Z","timestamp":1784192593000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-026-03741-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3741"],"URL":"https:\/\/doi.org\/10.1186\/s13046-026-03741-3","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"assertion":[{"value":"14 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The PDAC and liver metastases tissues used in this study were obtained from Huashan Hospital, Shanghai, with informed written consent from patients. The use of human specimens was approved by the Ethics Committee of Huashan Hospital, Fudan University (2022\u20131057). All animal studies were performed in accordance with guidelines provided by the Ethics Committee of Huashan Hospital, Fudan University (2025-HSYY-266). The animals were treated in accordance with relevant institutional and national guidelines and regulations.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors read and approved the final manuscript.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"163"}}