{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:58:53Z","timestamp":1785455933885,"version":"3.56.0"},"reference-count":33,"publisher":"Portland Press Ltd.","issue":"14","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Fondazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"crossref","award":["IG22835"],"award-info":[{"award-number":["IG22835"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007076","name":"Fondazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"crossref","award":["28919"],"award-info":[{"award-number":["28919"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"crossref","award":["M4C2I1.3 PE6 project PE00000019 Heal Italia (CUP H83C22000550006)"],"award-info":[{"award-number":["M4C2I1.3 PE6 project PE00000019 Heal Italia (CUP H83C22000550006)"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]},{"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":[[2024,7,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The high-grade serous ovarian cancer (HG-SOC) tumor microenvironment (TME) is constellated by cellular elements and a network of soluble constituents that contribute to tumor progression. In the multitude of the secreted molecules, the endothelin-1 (ET-1) has emerged to be implicated in the tumor\/TME interplay; however, the molecular mechanisms induced by the ET-1-driven feed-forward loops (FFL) and associated with the HG-SOC metastatic potential need to be further investigated. The tracking of the patient-derived (PD) HG-SOC cell transcriptome by RNA-seq identified the vascular endothelial growth factor (VEGF) gene and its associated signature among those mostly up-regulated by ET-1 and down-modulated by the dual ET-1R antagonist macitentan. Within the ligand\u2013receptor pairs concurrently expressed in PD-HG-SOC cells, endothelial cells and activated fibroblasts, we discovered two intertwined FFL, the ET-1\/ET-1R and VEGF\/VEGF receptors, concurrently activated by ET-1 and shutting-down by macitentan, or by the anti-VEGF antibody bevacizumab. In parallel, we observed that ET-1 fine-tuned the tumoral and stromal secretome toward a pro-invasive pattern. Into the fray of the HG-SOC\/TME double and triple co-cultures, the secretion of ET-1 and VEGF, that share a common co-regulation, was inhibited upon the administration of macitentan. Functionally, macitentan, mimicking the effect of bevacizumab, interfered with the HG-SOC\/TME FFL-driven communication that fuels the HG-SOC invasive behavior. The identification of ET-1 and VEGF FFL as tumor and TME actionable vulnerabilities, reveals how ET-1R blockade, targeting the HG-SOC cells and the TME simultaneously, may represent an effective therapeutic option for HG-SOC patients.<\/jats:p>","DOI":"10.1042\/cs20240346","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T14:18:58Z","timestamp":1718633938000},"page":"851-862","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The endothelin-1-driven tumor-stroma feed-forward loops in high-grade serous ovarian cancer"],"prefix":"10.1042","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-013X","authenticated-orcid":false,"given":"Piera","family":"Tocci","sequence":"first","affiliation":[{"name":"1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Roman","sequence":"additional","affiliation":[{"name":"1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (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":"1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Caprara","sequence":"additional","affiliation":[{"name":"1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sacconi","sequence":"additional","affiliation":[{"name":"2Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Molineris","sequence":"additional","affiliation":[{"name":"3Department of Life Science and System Biology, University of Turin, Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Tonon","sequence":"additional","affiliation":[{"name":"4Center for Omics Sciences (COSR) and Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy"},{"name":"5Universit\u00e0 Vita-Salute San Raffaele, 20132, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Blandino","sequence":"additional","affiliation":[{"name":"2Translational Oncology Research Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-9522","authenticated-orcid":false,"given":"Anna","family":"Bagnato","sequence":"additional","affiliation":[{"name":"1Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,7,5]]},"reference":[{"key":"2024070509302132100_B1","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1080\/14728222.2023.2259096","article-title":"Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap","volume":"27","author":"Bhat","year":"2023","journal-title":"Expert Opin. 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