| Literature DB >> 33527896 |
Maurizio Fazio1,2, Ellen van Rooijen1,2, Michelle Dang1,2, Glenn van de Hoek1, Julien Ablain1,2, Jeffrey K Mito1,3, Song Yang1, Andrew Thomas1, Jonathan Michael1, Tania Fabo1,2, Rodsy Modhurima1,2, Patrizia Pessina4, Charles K Kaufman5,6, Yi Zhou1,2, Richard M White7, Leonard I Zon1,2.
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.Entities:
Keywords: SATB2; cancer biology; drug resistance; epigenetics; melanoma; metastasis; neural crest; zebrafish
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Year: 2021 PMID： 33527896 PMCID： PMC7880683 DOI： 10.7554/eLife.64370
Source DB: PubMed Journal: Elife ISSN： 2050-084X Impact factor: 8.140