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To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:\n                    <jats:italic>BRAFV600E<\/jats:italic>\n                    ;\n                    <jats:italic>tp53-\/-<\/jats:italic>\n                    model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic\/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including\n                    <jats:italic>pdgfab<\/jats:italic>\n                    and\n                    <jats:italic>snai2<\/jats:italic>\n                    . The transcriptional program induced by SATB2 overlaps with known MITF\n                    <jats:sup>low<\/jats:sup>\n                    AXL\n                    <jats:sup>high<\/jats:sup>\n                    and AQP1\n                    <jats:sup>+<\/jats:sup>\n                    NGFR1\n                    <jats:sup>high<\/jats:sup>\n                    drug-resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. In summary, we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in autochthonous tumors.\n                  <\/jats:p>","DOI":"10.7554\/elife.64370","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T12:03:41Z","timestamp":1612267421000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64370","source":"Crossref","is-referenced-by-count":19,"title":["SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0083-6601","authenticated-orcid":true,"given":"Maurizio","family":"Fazio","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute, Stem Cell Program and the Division of Pediatric Hematology\/Oncology, Boston Children\u2019s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, United 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