{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T02:23:32Z","timestamp":1777083812581,"version":"3.51.4"},"posted":{"date-parts":[[2025,5,31]]},"group-title":"Cancer Biology","reference-count":23,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  A major challenge in melanoma treatment is the emergence of aggressive metastases from previously dormant disseminated cancer cells (DCCs). Here we identify Midkine (MDK) as a key factor that disrupts melanoma DCC dormancy by triggering an autocrine signal that suppresses the dormancy inducer NR2F1 and alters the p-p38\/p-ERK ratio, via ALK signaling. Dormant melanoma DCCs in lymph nodes and visceral tissues exhibit an MDK\n                  <jats:sup>LOW<\/jats:sup>\n                  \/NR2F1\n                  <jats:sup>HIGH<\/jats:sup>\n                  phenotype. Transient NR2F1 activation for one month with a potent agonist counteracts MDK-driven mTORC1 activity and suppresses lung metastasis in mice bearing human melanoma DCCs. Dual targeting of MDK (genetic blockade) and NR2F1 (activation) markedly limits metastatic outgrowth and extends survival for 6 months in mouse models independent of BRAF status. These findings support the MDK-NR2F1 axis as a promising therapeutic target to sustain dormancy and prevent melanoma recurrence.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>This work identifies Midkine as a key disruptor of tumor dormancy in melanoma, driving metastatic awakening via NR2F1 suppression. Dual targeting of Midkine (inhibition) and NR2F1 (activation) prolongs survival in preclinical models.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.27.656365","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T02:20:12Z","timestamp":1748744412000},"source":"Crossref","is-referenced-by-count":2,"title":["Midkine Drives Reawakening of Dormant Melanoma Metastases"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3853-7909","authenticated-orcid":false,"given":"Carolina","family":"Rodriguez-Tirado","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9529-6286","authenticated-orcid":false,"given":"Thoufiqul Alam","family":"Riaz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0583-2629","authenticated-orcid":false,"given":"Alcina A.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Rutgers University, Newark, NJ 07103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3185-8646","authenticated-orcid":false,"given":"Nupura","family":"Kale","sequence":"additional","affiliation":[{"name":"Helen Diller Comprehensive Family Cancer Center, University of San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3819-4485","authenticated-orcid":false,"given":"Ayax","family":"Perez-Gallegos","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5513-5621","authenticated-orcid":false,"given":"David","family":"Olmeda","sequence":"additional","affiliation":[{"name":"Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28049, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-6299","authenticated-orcid":false,"given":"Maria S.","family":"Soengas","sequence":"additional","affiliation":[{"name":"Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28049, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8783-3520","authenticated-orcid":false,"given":"Maria Soledad","family":"Sosa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042400550748000_2025.05.27.656365v2.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001604"},{"key":"2026042400550748000_2025.05.27.656365v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02674-y"},{"key":"2026042400550748000_2025.05.27.656365v2.3","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1995"},{"key":"2026042400550748000_2025.05.27.656365v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1073-3"},{"key":"2026042400550748000_2025.05.27.656365v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature22977"},{"key":"2026042400550748000_2025.05.27.656365v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7170"},{"key":"2026042400550748000_2025.05.27.656365v2.7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210836"},{"key":"2026042400550748000_2025.05.27.656365v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28076-3"},{"key":"2026042400550748000_2025.05.27.656365v2.9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2480"},{"key":"2026042400550748000_2025.05.27.656365v2.10","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-018-1049-0"},{"key":"2026042400550748000_2025.05.27.656365v2.11","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.4.863"},{"key":"2026042400550748000_2025.05.27.656365v2.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2578-6"},{"key":"2026042400550748000_2025.05.27.656365v2.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1704795"},{"key":"2026042400550748000_2025.05.27.656365v2.14","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.568814"},{"key":"2026042400550748000_2025.05.27.656365v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.062"},{"key":"2026042400550748000_2025.05.27.656365v2.16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00255"},{"key":"2026042400550748000_2025.05.27.656365v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03877-3"},{"key":"2026042400550748000_2025.05.27.656365v2.18","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.1966"},{"key":"2026042400550748000_2025.05.27.656365v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3465"},{"key":"2026042400550748000_2025.05.27.656365v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.09.002"},{"key":"2026042400550748000_2025.05.27.656365v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(83)90414-2"},{"key":"2026042400550748000_2025.05.27.656365v2.22","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.147.1.89"},{"key":"2026042400550748000_2025.05.27.656365v2.23","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9773-2_23"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.27.656365","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T07:55:14Z","timestamp":1777017314000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.27.656365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":23,"URL":"https:\/\/doi.org\/10.1101\/2025.05.27.656365","relation":{},"subject":[],"published":{"date-parts":[[2025,5,31]]},"subtype":"preprint"}}