{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T19:20:31Z","timestamp":1793215231065,"version":"4.5.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HG006137"],"award-info":[{"award-number":["R01HG006137"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Appendiceal mucinous neoplasms (AMN) are rare tumors of the gastrointestinal tract. They metastasize with widespread abdominal dissemination leading to pseudomyxoma peritonei (PMP), a disease with poor prognosis. There are many unknowns about the cellular features of origin, differentiation and progression of AMN and PMP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized AMNs, PMPs and matched normal tissues using single-cell RNA-sequencing. We validated our findings with immunohistochemistry, mass spectrometry on malignant ascites from PMP patients and gene expression data from an independent set of PMP tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified previously undescribed cellular features and heterogeneity in AMN and PMP tumors. There were gene expression signatures specific to the tumor epithelial cells among AMN and PMP. These signatures included genes indicative of goblet cell differentiation and elevated mucin gene expression. Metastatic PMP cells had a distinct gene expression signature with increased lipid metabolism, inflammatory, JAK-STAT and RAS signaling pathway among others. We observed clonal heterogeneity in a single PMP tumor as well as PMP metastases from the same patient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our study defined tumor cell gene signatures of AMN and PMP, successfully overcoming challenges of low cellularity and mucinous composition of these tumors. These gene expression signatures provide insights on tumor origin and differentiation, together with the identification of novel treatment targets. The heterogeneity observed within an individual tumor and between different tumors from the same patient, represents a potential source of treatment resistance.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1536982","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T07:10:12Z","timestamp":1739430612000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Distinct gene signatures define the epithelial cell features of mucinous appendiceal neoplasms and pseudomyxoma metastases"],"prefix":"10.3389","volume":"16","author":[{"given":"Carlos","family":"Ayala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuja","family":"Sathe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqi","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Grimes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Poultsides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byrne","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanlee P.","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/gm559","article-title":"Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin","volume":"6","author":"Alakus","year":"2014","journal-title":"Genome Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. 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