{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T03:56:34Z","timestamp":1782532594467,"version":"3.54.5"},"reference-count":29,"publisher":"Portland Press Ltd.","issue":"22","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana Ricerca sul Cancro","doi-asserted-by":"crossref","award":["IG22835"],"award-info":[{"award-number":["IG22835"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana Ricerca sul Cancro","doi-asserted-by":"crossref","award":["21327"],"award-info":[{"award-number":["21327"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"crossref"}]},{"name":"PRIN 2022 PNRR - European Union -Next Generation EU","award":["P2022Z7TEC"],"award-info":[{"award-number":["P2022Z7TEC"]}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"crossref","award":["RF-2019-12368718"],"award-info":[{"award-number":["RF-2019-12368718"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,11,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>High-grade serous ovarian cancer (HG-SOC), accounting for 70\u201380% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell\u2013cell interactions, and acellular components of the tumour microenvironment (TME). Within this tumour type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumour cells and stromal elements, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumouroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumouroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared with control cells, ET-1-stimulated tumouroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared with control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.<\/jats:p>","DOI":"10.1042\/cs20240371","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T14:03:56Z","timestamp":1730901836000},"page":"1441-1450","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumouroids"],"prefix":"10.1042","volume":"138","author":[{"given":"Judith","family":"Pape","sequence":"first","affiliation":[{"name":"1UCL Division of Surgery and Interventional Science, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umber","family":"Cheema","sequence":"additional","affiliation":[{"name":"1UCL Division of Surgery and Interventional Science, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-013X","authenticated-orcid":false,"given":"Piera","family":"Tocci","sequence":"additional","affiliation":[{"name":"2Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-2777","authenticated-orcid":false,"given":"Rosanna","family":"Sestito","sequence":"additional","affiliation":[{"name":"2Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Masi","sequence":"additional","affiliation":[{"name":"3Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Loizidou","sequence":"additional","affiliation":[{"name":"1UCL Division of Surgery and Interventional Science, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-9522","authenticated-orcid":false,"given":"Anna","family":"Bagnato","sequence":"additional","affiliation":[{"name":"2Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9962-6411","authenticated-orcid":false,"given":"Laura","family":"Rosan\u00f2","sequence":"additional","affiliation":[{"name":"2Unit of Preclinical Models and New Therapeutic Agents, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"},{"name":"3Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, 00185, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"2024111507364011400_B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"2024111507364011400_B2","doi-asserted-by":"publisher","first-page":"886533","DOI":"10.3389\/fendo.2022.886533","article-title":"The transcoelomic ecosystem and epithelial ovarian cancer dissemination","volume":"13","author":"Ritch","year":"2022","journal-title":"Front Endocrinol. (Lausanne)"},{"key":"2024111507364011400_B3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.matbio.2023.02.004","article-title":"Extracellular matrix in high-grade serous ovarian cancer: Advances in understanding of carcinogenesis and cancer biology","volume":"118","author":"Brown","year":"2023","journal-title":"Matrix Biol."},{"key":"2024111507364011400_B4","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nrc3546","article-title":"Endothelin 1 in cancer: biological implications and therapeutic opportunities","volume":"13","author":"Rosano","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"2024111507364011400_B5","doi-asserted-by":"publisher","first-page":"609","DOI":"10.3389\/fendo.2019.00609","article-title":"Targeting endothelin-1 receptor\/beta-Arrestin-1 Axis in ovarian cancer: from basic research to a therapeutic approach","volume":"10","author":"Tocci","year":"2019","journal-title":"Front Endocrinol. (Lausanne)"},{"key":"2024111507364011400_B6","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41419-022-05538-6","article-title":"Targeting tumour-stroma communication by blocking endothelin-1 receptors sensitizes high-grade serous ovarian cancer to PARP inhibition","volume":"14","author":"Tocci","year":"2023","journal-title":"Cell Death Dis."},{"key":"2024111507364011400_B7","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1038\/s41467-019-11045-8","article-title":"beta-arrestin1\/YAP\/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer","volume":"10","author":"Tocci","year":"2019","journal-title":"Nat. Commun."},{"key":"2024111507364011400_B8","doi-asserted-by":"publisher","first-page":"3132","DOI":"10.1073\/pnas.1715998115","article-title":"hMENA is a key regulator in endothelin-1\/beta-arrestin1-induced invadopodial function and metastatic process","volume":"115","author":"Di Modugno","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2024111507364011400_B9","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.matbio.2018.10.005","article-title":"Regulation of extracellular matrix degradation and metastatic spread by IQGAP1 through endothelin-1 receptor signalling in ovarian cancer","volume":"81","author":"Chellini","year":"2019","journal-title":"Matrix Biol."},{"key":"2024111507364011400_B10","doi-asserted-by":"publisher","first-page":"114","DOI":"10.3389\/fphar.2019.00114","article-title":"New Routes in GPCR\/beta-Arrestin-Driven signaling in cancer progression and metastasis","volume":"10","author":"Bagnato","year":"2019","journal-title":"Front Pharmacol."},{"key":"2024111507364011400_B11","doi-asserted-by":"publisher","first-page":"108800","DOI":"10.1016\/j.celrep.2021.108800","article-title":"Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK","volume":"34","author":"Masi","year":"2021","journal-title":"Cell Rep."},{"key":"2024111507364011400_B12","doi-asserted-by":"publisher","first-page":"3432","DOI":"10.1038\/onc.2015.403","article-title":"Endothelin A receptor drives invadopodia function and cell motility through the beta-arrestin\/PDZ-RhoGEF pathway in ovarian carcinoma","volume":"35","author":"Semprucci","year":"2016","journal-title":"Oncogene"},{"key":"2024111507364011400_B13","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41419-023-05612-7","article-title":"The interaction of beta-arrestin1 with talin1 driven by endothelin A receptor as a feature of alpha5beta1 integrin activation in high-grade serous ovarian cancer","volume":"14","author":"Masi","year":"2023","journal-title":"Cell Death Dis."},{"key":"2024111507364011400_B14","doi-asserted-by":"publisher","first-page":"764375","DOI":"10.3389\/fcell.2021.764375","article-title":"Ovarian cancer-driven mesothelial-to-mesenchymal transition is triggered by the endothelin-1\/beta-arr1 Axis","volume":"9","author":"Del Rio","year":"2021","journal-title":"Front Cell Dev. Biol."},{"key":"2024111507364011400_B15","doi-asserted-by":"publisher","first-page":"189052","DOI":"10.1016\/j.bbcan.2023.189052","article-title":"The high-grade serous ovarian cancer metastasis and chemoresistance in 3D models","volume":"1879","author":"Tadic","year":"2024","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"2024111507364011400_B16","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1007\/s12079-022-00666-2","article-title":"Renal tumouroids: challenges of manufacturing 3D cultures from patient derived primary cells","volume":"16","author":"Nyga","year":"2022","journal-title":"J. Cell Commun. Signal."},{"issue":"8","key":"2024111507364011400_B17","doi-asserted-by":"publisher","first-page":"4289","DOI":"10.3390\/ijms22084289","article-title":"Tissue-engineering the fibrous pancreatic tumour stroma capsule in 3D tumouroids to demonstrate paclitaxel response","volume":"22","author":"Pape","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2024111507364011400_B18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.ejca.2019.07.005","article-title":"Cancer invasion regulates vascular complexity in a three-dimensional biomimetic model","volume":"119","author":"Pape","year":"2019","journal-title":"Eur. J. Cancer"},{"issue":"2","key":"2024111507364011400_B19","doi-asserted-by":"publisher","first-page":"572","DOI":"10.3390\/biomedicines11020572","article-title":"Treatment of 3D In Vitro Tumoroids of Ovarian Cancer Using Photochemical Internalisation as a Drug Delivery Method","volume":"11","author":"Mohammad Hadi","year":"2023","journal-title":"Biomedicines"},{"key":"2024111507364011400_B20","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1002\/adfm.200500042","article-title":"Ultrarapid engineering of biomimetic materials and tissues: Fabrication of nano- and microstructures by plastic compression","volume":"15","author":"Brown","year":"2005","journal-title":"Adv. Funct. Mater."},{"key":"2024111507364011400_B21","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/S0140-6736(18)32552-2","article-title":"Epithelial ovarian cancer","volume":"393","author":"Lheureux","year":"2019","journal-title":"Lancet"},{"key":"2024111507364011400_B22","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/s41571-023-00819-1","article-title":"Heterogeneity and treatment landscape of ovarian carcinoma","volume":"20","author":"Veneziani","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2024111507364011400_B23","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.trecan.2020.10.009","article-title":"3D In vitro model (R)evolution: unveiling tumour-stroma interactions","volume":"7","author":"Rodrigues","year":"2021","journal-title":"Trends Cancer"},{"key":"2024111507364011400_B24","doi-asserted-by":"publisher","first-page":"115152","DOI":"10.1016\/j.biopha.2023.115152","article-title":"The response and resistance to drugs in ovarian cancer cell lines in 2D monolayers and 3D spheroids","volume":"165","author":"Swierczewska","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"2024111507364011400_B25","doi-asserted-by":"publisher","first-page":"836984","DOI":"10.3389\/fbioe.2022.836984","article-title":"Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine","volume":"10","author":"Yee","year":"2022","journal-title":"Front Bioeng. Biotechnol."},{"key":"2024111507364011400_B26","doi-asserted-by":"publisher","first-page":"24088","DOI":"10.1038\/s41598-021-03484-5","article-title":"Bioengineering the ameloblastoma tumour to study its effect on bone nodule formation","volume":"11","author":"Bakkalci","year":"2021","journal-title":"Sci. Rep."},{"key":"2024111507364011400_B27","doi-asserted-by":"publisher","first-page":"3729","DOI":"10.1021\/acsbiomaterials.0c01530","article-title":"3D In vitro models for investigating the role of stiffness in cancer invasion","volume":"9","author":"Micalet","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"issue":"8","key":"2024111507364011400_B28","doi-asserted-by":"publisher","first-page":"4010","DOI":"10.3390\/ijms22084010","article-title":"Evaluating oxygen tensions related to bone marrow and matrix for MSC differentiation in 2D and 3D biomimetic lamellar scaffolds","volume":"22","author":"Sayin","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2024111507364011400_B29","doi-asserted-by":"publisher","first-page":"2041731420920597","DOI":"10.1177\/2041731420920597","article-title":"The anti-angiogenic tyrosine kinase inhibitor Pazopanib kills cancer cells and disrupts endothelial networks in biomimetic three-dimensional renal tumouroids","volume":"11","author":"Stamati","year":"2020","journal-title":"J. Tissue Eng."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/22\/1441\/963310\/cs-2024-0371.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/22\/1441\/963310\/cs-2024-0371.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T07:37:13Z","timestamp":1731656233000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/138\/22\/1441\/235215\/Endothelin-1-receptor-blockade-impairs-invasion"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11]]},"references-count":29,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2024,11,20]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20240371","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,11]]}}}