{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T02:05:09Z","timestamp":1768442709241,"version":"3.49.0"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T00:00:00Z","timestamp":1547078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012538","name":"Swedish Cancer Foundation","doi-asserted-by":"publisher","award":["17 0537"],"award-info":[{"award-number":["17 0537"]}],"id":[{"id":"10.13039\/100012538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003461","name":"Gunnar Nilssons Cancerstiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003461","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011077","name":"Sk\u00e5nes universitetssjukhus","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011077","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005753","name":"Kungliga Fysiografiska S\u00e4llskapet i Lund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005753","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2015\u201002540"],"award-info":[{"award-number":["2015\u201002540"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:p>The identification of novel antimetastatic therapeutic targets is necessary for improved treatment of patients with acquired <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> inhibitor\u2010resistant (<jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R) melanoma, in whom metastasis is a major concern. Our present study focused on the identification of such targets to explore novel antimetastatic therapeutic options for <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma patients. We confirmed the development of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i resistance in our <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010treated melanoma cell lines by demonstrating reduced sensitivity to <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> inhibitors, increased <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 activity and increased <jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A expression. Here, we demonstrated for the first time that high secretion of interleukin\u20106 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106) was associated with increased invasive migration of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells. This finding could be readily explained by the increased expression of <jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A in <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells and the presence of an <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106\/<jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A positive feedback loop in parental melanoma cells. Surprisingly, however, we found that the <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106\/<jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A positive feedback loop present in parental melanoma cells was lost during the development of acquired <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i resistance, meaning that <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106 and <jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A signalling were independent events in <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells. Despite the absence of an <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106\/<jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A loop, we found that both an <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106 blocking antibody and the <jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A antagonist Box5 alone impaired the elevated invasive migration of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells, but combined use of the two was more effective. This impaired invasive migration of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells correlated well with the reduction in Cdc42\u2010<jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>ase activity and alterations of the actin cytoskeleton in these cells. In summary, our novel identification of <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106 as a key independent promoter of the invasive migration of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma cells stresses that a combination of a blocking <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106 antibody and administration of the <jats:styled-content style=\"fixed-case\">WNT<\/jats:styled-content>5A antagonist Box5 might be an attractive antimetastatic approach for future treatment of <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content>i\u2010R melanoma patients.<\/jats:p>","DOI":"10.1002\/1878-0261.12433","type":"journal-article","created":{"date-parts":[[2018,12,24]],"date-time":"2018-12-24T16:40:52Z","timestamp":1545669652000},"page":"480-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Combination therapy targeting the elevated interleukin\u20106 level reduces invasive migration of <scp>BRAF<\/scp> inhibitor\u2010resistant melanoma cells"],"prefix":"10.1002","volume":"13","author":[{"given":"Purusottam","family":"Mohapatra","sequence":"first","affiliation":[{"name":"Cell and Experimental Pathology Department of Translational Medicine Clinical Research Centre Sk\u00e5ne University Hospital Lund University Malm\u00f6 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandra Prakash","family":"Prasad","sequence":"additional","affiliation":[{"name":"Cell and Experimental Pathology Department of Translational Medicine Clinical Research Centre Sk\u00e5ne University Hospital Lund University Malm\u00f6 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommy","family":"Andersson","sequence":"additional","affiliation":[{"name":"Cell and Experimental Pathology Department of Translational Medicine Clinical Research Centre Sk\u00e5ne University Hospital Lund University Malm\u00f6 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,1,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70156"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0842"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13572"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-148X.2010.00792.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-5104"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2008.08.053"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0682"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909409106"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12307-011-0087-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01572-13"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2014.05.008"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9332"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0000000000000021"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.028498"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0005"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2013.04.005"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers7030868"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.07.010"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2011.04.001"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1875"},{"key":"e_1_2_10_22_1","unstructured":"SurviladzeZ WallerA StrouseJJ BologaC UrsuO SalasV ParkinsonJF PhillipsGK RomeroE Wandinger\u2010NessAet\u00a0al. (2010)A potent and selective inhibitor of Cdc42 GTPase probe reports from the NIH molecular libraries program Bethesda (MD)."},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711741105"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2007.08246.x"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2017.07.002"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.418"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00045-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23040787"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2006.07.001"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2F1878-0261.12433","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.12433","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.12433","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.12433","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T09:58:21Z","timestamp":1694685501000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.12433"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,10]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1002\/1878-0261.12433"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.12433","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,10]]},"assertion":[{"value":"2018-10-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}