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This study aimed to establish an orthotopic model of PDAC peritoneal dissemination and to uncover the transcriptional and regulatory programs underlying this process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Organoids were established from primary pancreatic tumors and malignant effusions of patients with PDAC and orthotopically transplanted into the pancreas of immunodeficient mice to generate patient-derived orthotopic xenograft (PDOX) models. Subsequently, the organoids were rederived from pancreatic and peritoneal lesions of a representative model (PDOX12) and orthotopically reimplanted to assess the dissemination capacity. Single-nucleus RNA sequencing (snRNA-seq) and single-cell ATAC sequencing (scATAC-seq) were performed to analyze the tumors from these models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The organoids that were derived from malignant effusions reproducibly generated peritoneal metastases after orthotopic implantation. To dissect this process more precisely, we focused on one representative model (PDOX12) and rederived organoids from its pancreatic and peritoneal lesions. These organoids generated matched PDOX models that differed only in dissemination potential when reimplanted orthotopically. The results of snRNA-seq revealed a distinct subpopulation enriched in the high-dissemination model, which was characterized by the coordinated activation of genes involved in cytoskeletal dynamics, extracellular matrix remodeling, and plasticity-related signaling\u2014suggesting a dissemination-primed state. Integration with scATAC-seq identified STAT3, SMAD3, and SOX2 as potential upstream regulators of this gene program.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03668-9","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T08:43:47Z","timestamp":1770799427000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient-derived orthotopic xenograft models recapitulate the peritoneal dissemination of pancreatic cancer and delineate its transcriptional and regulatory programs"],"prefix":"10.1186","volume":"45","author":[{"given":"Takaaki","family":"Furukawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kumegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Miyata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Takamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asumi","family":"Iesato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumito","family":"Saeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikako","family":"Shibata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Takahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Mie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Ozaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwa","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoji","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Sasahira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reo","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"3668_CR1","doi-asserted-by":"crossref","unstructured":"Wu G, Standring OJ, King DA et al. 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All procedures involving human samples were approved by the Institutional Review Board of the Japanese Foundation for Cancer Research (2017-GA-1129 and 2025-GB-070). All animal experiments were performed under protocols that was approved by the Institutional Animal Care and Use Committee of the JFCR (no. 22-01-2).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from all patients whose samples and data are included in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"69"}}