Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa: BRAFV600E ; tp53-/- 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 pdgfab and snai2 . The transcriptional program induced by SATB2 overlaps with known MITF low AXL high and AQP1 + NGFR1 high 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.
Competing Interests: MF, Ev, MD, Gv, JA, JM, SY, AT, JM, TF, RM, PP, CK, YZ No competing interests declared, RW Senior editor, eLife, LZ LIZ is a founder and stockholder of Fate Therapeutics Inc, Scholar Rock Inc, Camp4 Therapeutics Inc, Amagma Therapeutics Inc, and a scientific advisor for Stemgent.
(© 2021, Fazio et al.)