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Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin\/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging.<\/jats:p><\/jats:sec>","DOI":"10.1038\/s41416-021-01442-6","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T09:03:03Z","timestamp":1624611783000},"page":"699-713","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma"],"prefix":"10.1038","volume":"125","author":[{"given":"Oscar","family":"Maiques","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Fanshawe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Crosas-Molist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-452X","authenticated-orcid":false,"given":"Irene","family":"Rodriguez-Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Volpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Cantelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-7533","authenticated-orcid":false,"given":"Lena","family":"Boehme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose L.","family":"Orgaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraz K.","family":"Mardakheh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-9456","authenticated-orcid":false,"given":"Victoria","family":"Sanz-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-2674","authenticated-orcid":false,"given":"Gilbert O.","family":"Fruhwirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"1442_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan, D. & Weinberg, R. 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All patient data were already publicly available in the National Cancer Institute\u2019s TCGA and NCBI\u2019s GEO databases. TCGA Ethics & Policies was originally published by the National Cancer Institute. Individual ethics approval and consent information of GEO datasets can be found in the respective datasets using the GEO Accession Viewer. Animals: All experimental protocols were monitored and approved by the King\u2019s College London Animal Welfare and Ethical Review Body Animal Welfare and Ethical Review Panel, in accordance with UK Home Office regulations (Project License 70\/8879) under the Animals (Scientific Procedures) Act 1986 and UK National Cancer Research Institute (NCRI) Guidelines for the Welfare and Use of Animals in Cancer Research.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Patient data were from publicly available databases; please see there for details regarding consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"Gene expression datasets re-analysed in this study are available from TCGA and NCBI GEO under accession numbers: GSE4570, GSE4840, GSE4843, GSE4841, GSE23764, GSE8401, GSE7553 and GSE46517.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"GOF\u2019s lab was supported by Cancer Research UK [C48390\/A21153], Worldwide Cancer Research [16-1153], and King\u2019s Health Partners [King\u2019s Medical Research Trust Joint Research Committee studentship to A.V.]. B.F. was supported by a King\u2019s Health Partners studentship to V.S.M. and G.O.F. V.S.M.\u2019s lab was supported by Cancer Research UK [C33043\/A12065] and [C33043\/A24478] (V.S.M., E.C.M., J.L.O., L.B. and GC), the Royal Society [RG110591] (V.S.M.), The Harry J. Lloyd Charitable Trust (J.L.O. and V.S.M.), the Barts Charity (V.S.M., J.L.O., O.M., I.R.H. and E.C.M.), the Fundacion Alfonso Martin Escudero and Marie Sklodowska-Curie Action [H2020-MSCA-IF-2014-EF-ST] (I.R.H.), and Fundacion Ramon Areces (E.C.M.). F.M. was supported by an MRC Career Development Award (MR\/P009417\/1). This work was further supported by the Department of Health (DoH) via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to King\u2019s Health Partners, and the Wellcome\/EPSRC Centre for Medical Engineering [WT203148\/Z\/16\/Z]. Views expressed are those of the authors and not necessarily those of the NHS, NIHR or DoH.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}