Satb2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance

Maurizio Fazio, Ellen van Rooijen, Michelle Dang, Glenn van de Hoek, Julien Ablain, Jeffrey K. Mito, Song Yang, Andrew Thomas, Jonathan Michael, Tania Fabo, Rodsy Modhurima, Patrizia Pessina, Charles K. Kaufman, Yi Zhou, Richard M. White, Leonard I. Zon

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 MITFlowAXLhigh and AQP1+NGFR1high 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.

Original languageEnglish
Article numbere64370
Pages (from-to)1-28
Number of pages28
JournaleLife
Volume10
DOIs
StatePublished - Feb 2021

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