{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:41:38Z","timestamp":1785426098528,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,13]]},"group-title":"Cancer Biology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01CA242021"],"award-info":[{"award-number":["R01CA242021"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA230628"],"award-info":[{"award-number":["R01CA230628"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50CA272218"],"award-info":[{"award-number":["P50CA272218"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA047904"],"award-info":[{"award-number":["P30CA047904"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Department of Defense Ovarian Cancer Research Program","award":["HT94252310207"],"award-info":[{"award-number":["HT94252310207"]}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["2T32HL110849-11A1"],"award-info":[{"award-number":["2T32HL110849-11A1"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  All ovarian cancer subtypes spread via transcoelomic metastasis, where cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This represents the main driver of morbidity and mortality for peritoneal cancer patients. Mechanisms necessary for cancer cells to survive matrix detachment and initiate transcoelomic metastasis remain poorly defined. To address this, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived cancer cell lines. RHOV, an atypical, constitutively active and understudied member of the Rho GTPase family, emerged as a top upregulated transcript, which was confirmed in patient ascites-derived tumor cells. Functionally, loss of RHOV impairs anoikis resistance, multicellular aggregate integrity, migration and invasion, and completely abolishes transcoelomic tumor progression\n                  <jats:italic>in vivo<\/jats:italic>\n                  . RHOV enhances c-Jun signaling and cytoskeletal remodeling, which is dependent on both RHOV GTP-binding and membrane localization. These findings define RHOV as a novel detachment-sensitive Rho GTPase and establish RHOV as a critical regulator of peritoneal metastasis for the first time.\n                <\/jats:p>","DOI":"10.1101\/2025.08.12.669944","type":"posted-content","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T16:10:16Z","timestamp":1755101416000},"source":"Crossref","is-referenced-by-count":0,"title":["RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6547-3018","authenticated-orcid":false,"given":"Amal T.","family":"Elhaw","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6081-4001","authenticated-orcid":false,"given":"Priscilla W.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2472-0577","authenticated-orcid":false,"given":"Ya-Yun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2686-3387","authenticated-orcid":false,"given":"Shriya","family":"Kamlapurkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1336-2564","authenticated-orcid":false,"given":"Zaineb","family":"Javed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4125-5047","authenticated-orcid":false,"given":"Sarah","family":"Al-Saad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0764-9585","authenticated-orcid":false,"given":"Sierra R.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-3643","authenticated-orcid":false,"given":"Ahmed Emam","family":"Abdelnaby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5410-6906","authenticated-orcid":false,"given":"Alex Seok","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-0848","authenticated-orcid":false,"given":"Aidan R.","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon-Soo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda I.","family":"Atiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-864X","authenticated-orcid":false,"given":"Mohamed","family":"Trebak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2386-9553","authenticated-orcid":false,"given":"Ioannis","family":"Zervantonakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5665-9790","authenticated-orcid":false,"given":"Ronald J.","family":"Buckanovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5828-2325","authenticated-orcid":false,"given":"Katherine M.","family":"Aird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3753-1652","authenticated-orcid":false,"given":"Lan G.","family":"Coffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5478-0098","authenticated-orcid":false,"given":"Karthikeyan","family":"Mythreye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5574-8783","authenticated-orcid":false,"given":"Nadine","family":"Hempel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081421451028000_2025.08.12.669944v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"2025081421451028000_2025.08.12.669944v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(06)70939-1"},{"key":"2025081421451028000_2025.08.12.669944v1.3","doi-asserted-by":"crossref","unstructured":"Rickard BP , Conrad C , Sorrin AJ , Ruhi MK , Reader JC , Huang SA , et al. Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response. Cancers (Basel). 2021;13(17).","DOI":"10.3390\/cancers13174318"},{"issue":"5","key":"2025081421451028000_2025.08.12.669944v1.4","doi-asserted-by":"crossref","first-page":"546","DOI":"10.4149\/neo_2013_071","article-title":"Clinical significance of ascites in epithelial ovarian cancer","volume":"60","year":"2013","journal-title":"Neoplasma"},{"issue":"25","key":"2025081421451028000_2025.08.12.669944v1.5","first-page":"3315","article-title":"Anoikis resistance is a critical feature of highly aggressive ovarian cancer cells","volume":"34","year":"2014","journal-title":"Oncogene"},{"issue":"8","key":"2025081421451028000_2025.08.12.669944v1.6","doi-asserted-by":"crossref","first-page":"4222","DOI":"10.3390\/ijms22084222","article-title":"Malignant Ascites Promote Adhesion of Ovarian Cancer Cells to Peritoneal Mesothelium and Fibroblasts","volume":"22","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"2025081421451028000_2025.08.12.669944v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-0875-x"},{"key":"2025081421451028000_2025.08.12.669944v1.8","doi-asserted-by":"crossref","unstructured":"Farsinejad S , Cattabiani T , Muranen T , Iwanicki M . Ovarian Cancer Dissemination-A Cell Biologist\u2019s Perspective. Cancers (Basel). 2019;11(12).","DOI":"10.3390\/cancers11121957"},{"issue":"1","key":"2025081421451028000_2025.08.12.669944v1.9","first-page":"1","article-title":"Disaggregation and invasion of ovarian carcinoma ascites spheroids","volume":"4","year":"2006","journal-title":"Journal of Translational Medicine"},{"key":"2025081421451028000_2025.08.12.669944v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2008.11.032"},{"key":"2025081421451028000_2025.08.12.669944v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0317-x"},{"key":"2025081421451028000_2025.08.12.669944v1.12","doi-asserted-by":"publisher","DOI":"10.1042\/bj20031041"},{"key":"2025081421451028000_2025.08.12.669944v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nrc725"},{"key":"2025081421451028000_2025.08.12.669944v1.14","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00045.2020"},{"key":"2025081421451028000_2025.08.12.669944v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20327"},{"key":"2025081421451028000_2025.08.12.669944v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.11.011"},{"issue":"1","key":"2025081421451028000_2025.08.12.669944v1.17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1080\/21541248.2017.1362495","article-title":"Regulation and functions of RhoU and RhoV","volume":"11","year":"2020","journal-title":"Small GTPases"},{"key":"2025081421451028000_2025.08.12.669944v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(06)06002-2"},{"key":"2025081421451028000_2025.08.12.669944v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.07.031"},{"issue":"4","key":"2025081421451028000_2025.08.12.669944v1.20","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1080\/21541248.2015.1025943","article-title":"Atypical RhoV and RhoU GTPases control development of the neural crest","volume":"6","year":"2015","journal-title":"Small GTPases"},{"key":"2025081421451028000_2025.08.12.669944v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010125"},{"key":"2025081421451028000_2025.08.12.669944v1.22","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.59939"},{"key":"2025081421451028000_2025.08.12.669944v1.23","doi-asserted-by":"crossref","unstructured":"Chen H , Xia R , Jiang L , Zhou Y , Xu H , Peng W , et al. Overexpression of RhoV Promotes the Progression and EGFR-TKI Resistance of Lung Adenocarcinoma. Front Oncol. 2021;11:619013.","DOI":"10.3389\/fonc.2021.619013"},{"key":"2025081421451028000_2025.08.12.669944v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2013.10.006"},{"issue":"6","key":"2025081421451028000_2025.08.12.669944v1.25","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1111\/cas.15783","article-title":"In vivo CRISPR screens identify RhoV as a pro-metastasis factor of triple-negative breast cancer","volume":"114","year":"2023","journal-title":"Cancer Sci"},{"issue":"8","key":"2025081421451028000_2025.08.12.669944v1.26","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1038\/s41388-019-1097-7","article-title":"Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells","volume":"39","year":"2020","journal-title":"Oncogene"},{"issue":"4","key":"2025081421451028000_2025.08.12.669944v1.27","doi-asserted-by":"crossref","first-page":"111066","DOI":"10.1016\/j.celrep.2022.111066","article-title":"Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer","volume":"40","year":"2022","journal-title":"Cell Rep"},{"key":"2025081421451028000_2025.08.12.669944v1.28","unstructured":"28. DepMap Public 25Q2 [Internet]. Broad. 2025. Available from: depmap.org."},{"key":"2025081421451028000_2025.08.12.669944v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"2025081421451028000_2025.08.12.669944v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3126"},{"key":"2025081421451028000_2025.08.12.669944v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.09.016"},{"key":"2025081421451028000_2025.08.12.669944v1.32","doi-asserted-by":"crossref","unstructured":"Capellero S , Erriquez J , Battistini C , Porporato R , Scotto G , Borella F , et al. Ovarian Cancer Cells in Ascites Form Aggregates That Display a Hybrid Epithelial-Mesenchymal Phenotype and Allows Survival and Proliferation of Metastasizing Cells. Int J Mol Sci. 2022;23(2).","DOI":"10.3390\/ijms23020833"},{"key":"2025081421451028000_2025.08.12.669944v1.33","doi-asserted-by":"crossref","unstructured":"Goyeneche A , Lisio MA , Fu L , Srinivasan R , Valdez Capuccino J , Gao ZH , et al. The Capacity of High-Grade Serous Ovarian Cancer Cells to Form Multicellular Structures Spontaneously along Disease Progression Correlates with Their Orthotopic Tumorigenicity in Immunosuppressed Mice. Cancers (Basel). 2020;12(3).","DOI":"10.3390\/cancers12030699"},{"key":"2025081421451028000_2025.08.12.669944v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24188"},{"key":"2025081421451028000_2025.08.12.669944v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2017.04.002"},{"key":"2025081421451028000_2025.08.12.669944v1.36","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8274.CD-11-0010"},{"key":"2025081421451028000_2025.08.12.669944v1.37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69815"},{"issue":"6","key":"2025081421451028000_2025.08.12.669944v1.38","doi-asserted-by":"crossref","first-page":"109950","DOI":"10.1016\/j.isci.2024.109950","article-title":"Enhancing PKA-dependent mesothelial barrier integrity reduces ovarian cancer transmesothelial migration via inhibition of contractility","volume":"27","year":"2024","journal-title":"iScience"},{"key":"2025081421451028000_2025.08.12.669944v1.39","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-11-0117"},{"key":"2025081421451028000_2025.08.12.669944v1.40","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2020.5153"},{"issue":"1","key":"2025081421451028000_2025.08.12.669944v1.41","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41420-024-01886-8","article-title":"Serpine1 mRNA confers mesenchymal characteristics to the cell and promotes CD8+ T cells exclusion from colon adenocarcinomas","volume":"10","year":"2024","journal-title":"Cell Death Discov"},{"issue":"27","key":"2025081421451028000_2025.08.12.669944v1.42","first-page":"41095","article-title":"Proteinase-activated receptor 2 promotes TGF-beta-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-beta type I receptor ALK5","volume":"7","year":"2016","journal-title":"Oncotarget"},{"issue":"4","key":"2025081421451028000_2025.08.12.669944v1.43","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10238-018-0509-2","article-title":"MYLK promotes hepatocellular carcinoma progression through regulating cytoskeleton to enhance epithelial-mesenchymal transition","volume":"18","year":"2018","journal-title":"Clin Exp Med"},{"key":"2025081421451028000_2025.08.12.669944v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63058-1"},{"key":"2025081421451028000_2025.08.12.669944v1.45","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-021-10136-5"},{"key":"2025081421451028000_2025.08.12.669944v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25589-0"},{"key":"2025081421451028000_2025.08.12.669944v1.47","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2001.5180"},{"key":"2025081421451028000_2025.08.12.669944v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(98)70468-3"},{"key":"2025081421451028000_2025.08.12.669944v1.49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411300200"},{"issue":"4","key":"2025081421451028000_2025.08.12.669944v1.50","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1134\/S002689331804009X","article-title":"Mutations in the Effector Domain of RhoV GTPase Impair Its Binding to Pak1 Protein Kinase","volume":"52","year":"2018","journal-title":"Molecular Biology"},{"key":"2025081421451028000_2025.08.12.669944v1.51","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297912010038"},{"key":"2025081421451028000_2025.08.12.669944v1.52","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20061696"},{"key":"2025081421451028000_2025.08.12.669944v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.12.014"},{"key":"2025081421451028000_2025.08.12.669944v1.54","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-4151"},{"issue":"1","key":"2025081421451028000_2025.08.12.669944v1.55","first-page":"219","article-title":"MUC16 mucin (CA125) regulates the formation of multicellular aggregates by altering beta-catenin signaling","volume":"5","year":"2015","journal-title":"Am J Cancer Res"},{"issue":"2","key":"2025081421451028000_2025.08.12.669944v1.56","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s13277-010-0017-9","article-title":"Initial formation of IGROV1 ovarian cancer multicellular aggregates involves vitronectin","volume":"31","year":"2010","journal-title":"Tumor Biology"},{"key":"2025081421451028000_2025.08.12.669944v1.57","doi-asserted-by":"crossref","unstructured":"Minatohara K , Akiyoshi M , Okuno H . Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace. Front Mol Neurosci. 2015;8:78.","DOI":"10.3389\/fnmol.2015.00078"},{"key":"2025081421451028000_2025.08.12.669944v1.58","doi-asserted-by":"crossref","unstructured":"Luu AP , Yao Z , Ramachandran S , Azzopardi SA , Miles LA , Schneider WM , et al. A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry. Viruses. 2021;13(11).","DOI":"10.3390\/v13112113"},{"key":"2025081421451028000_2025.08.12.669944v1.59","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-09-0896"},{"key":"2025081421451028000_2025.08.12.669944v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.328"},{"key":"2025081421451028000_2025.08.12.669944v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"2025081421451028000_2025.08.12.669944v1.62","doi-asserted-by":"crossref","unstructured":"Kim YS , Tang PW , Welles JE , Pan W , Javed Z , Elhaw AT , et al. HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence. Redox Biol. 2022;53:102329.","DOI":"10.1016\/j.redox.2022.102329"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.12.669944","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:11:48Z","timestamp":1782277908000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.12.669944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":62,"URL":"https:\/\/doi.org\/10.1101\/2025.08.12.669944","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1158\/0008-5472.CAN-25-4056","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,8,13]]},"subtype":"preprint"}}