SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33527896.
- Also identified by DOI 10.7554/eLife.64370 and PMC identifier 7880683.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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:<i>BRAFV600E</i>;<i>tp53-/-</i> 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 <i>pdgfab</i> and <i>snai2</i>. The transcriptional program induced by SATB2 overlaps with known MITF<sup>low</sup>AXL<sup>high</sup> and AQP1<sup>+</sup>NGFR1<sup>high</sup> 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.
Medical subject headings
- Drug Resistance, Neoplasm
- Matrix Attachment Region Binding Proteins
- Melanoma
- Neoplasm Invasiveness
- Transcription Factors
- Zebrafish Proteins