PT  - JOURNAL ARTICLE
AU  - Maurizio Fazio
AU  - Ellen van Rooijen
AU  - Michelle Dang
AU  - Glenn van de Hoek
AU  - Julien Ablain
AU  - Jeffrey K. Mito
AU  - Song Yang
AU  - Andrew Thomas
AU  - John Michael
AU  - Tania Fabo
AU  - Rodsy Modhurima
AU  - Patrizia Pessina
AU  - Charles Kaufman
AU  - Yi Zhou
AU  - Richard M. White
AU  - Leonard I. Zon
TI  - SATB2 induction of a neural crest mesenchyme-like program drives invasion and drug resistance in melanoma
AID  - 10.1101/2020.11.01.364406
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.01.364406
4099  - http://biorxiv.org/content/early/2020/11/02/2020.11.01.364406.short
4100  - http://biorxiv.org/content/early/2020/11/02/2020.11.01.364406.full
AB  - Recent genomic and scRNA-seq analyses of melanoma identified common transcriptional states correlating with invasion or drug resistance, but failed to find recurrent drivers of metastasis. 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 MITFlowAXLhlgh and AQP1+NGFR1high drug resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. Here we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in endogenous tumors.