{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:38:35Z","timestamp":1753871915160,"version":"3.41.2"},"reference-count":29,"publisher":"Portland Press Ltd.","issue":"12","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"crossref","award":["IG22835"],"award-info":[{"award-number":["IG22835"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"crossref","award":["MFAG 2023 ID. 28919"],"award-info":[{"award-number":["MFAG 2023 ID. 28919"]}],"id":[{"id":"10.13039\/100020581","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":[[2024,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The high-grade serous ovarian cancer (HG-SOC) is a notoriously challenging disease, characterized by a rapid peritoneal dissemination. HG-SOC cells leverage actin-rich membrane protrusions, known as invadopodia, to degrade the surrounding extracellular matrix (ECM) and invade, initiating the metastatic cascade. In HG-SOC, the endothelin-1 (ET-1)\/endothelin A receptor (ETAR)-driven signaling coordinates invadopodia activity, however how this axis integrates pro-oncogenic signaling routes, as YAP-driven one, impacting on the invadopodia-mediated ECM degradation and metastatic progression, deserves a deeper investigation. Herein, we observed that downstream of the ET-1\/ET-1R axis, the RhoC and Rac1 GTPases, acting as signaling intermediaries, promote the de-phosphorylation and nuclear accumulation of YAP. Conversely, the treatment with the dual ETA\/ETB receptor antagonist, macitentan, inhibits the ET-1-driven YAP activity. Similarly, RhoC silencing, or cell transfection with a dominant inactive form of Rac1, restores YAP phosphorylation. Mechanistically, the ET-1R\/YAP signal alliance coordinates invadopodia maturation into ECM-degrading structures, indicating how such ET-1R-guided protein network represents a route able to enhance the HG-SOC invasive potential. At functional level, we found that the interconnection between the ET-1R\/RhoC and YAP signals is required for MMP-2 and MMP-9 proteolytic functions, cell invasion, and cytoskeleton architecture changes, supporting the HG-SOC metastatic strength. In HG-SOC patient-derived xenografts (PDX) macitentan, turning-off the invadopodia regulators RhoC\/YAP, halts the metastatic colonization. ET-1R targeting, hindering the YAP activity, weakens the invadopodia machinery, embodying a promising therapeutic avenue to prevent peritoneal dissemination in HG-SOC.<\/jats:p>","DOI":"10.1042\/bsr20241320","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T17:17:31Z","timestamp":1730740651000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["YAP signaling orchestrates the endothelin-1-guided invadopodia formation in high-grade serous ovarian cancer"],"prefix":"10.1042","volume":"44","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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Rosan\u00f2","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"},{"name":"2Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome 00185, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,11,29]]},"reference":[{"key":"2024112913001424300_B1","doi-asserted-by":"publisher","first-page":"e174013","DOI":"10.1172\/JCI174013","article-title":"Biology-driven therapy advances in high-grade serous ovarian cancer","volume":"134","author":"Wang","year":"2024","journal-title":"J. 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