Fazio M, van Rooijen E, Dang M, van de Hoek G, Ablain J, Mito JK, Yang S, Thomas A, Michael J, Fabo T, Modhurima R, Pessina P, Kaufman CK, Zhou Y, White RM, Zon LI. 2021. SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance. eLife. 10. Pubmed: 33527896 DOI:10.7554/eLife.64370


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:; 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 and . The transcriptional program induced by SATB2 overlaps with known MITFAXL and AQP1NGFR1 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.
© 2021, Fazio et al.

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Photo of Len Zon

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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