SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance
- Boston Children's Hospital, United States
- Brigham and Women's Hospital, United States
- Washington University School of Medicine, United States
- Memorial Sloan Kettering Cancer Center, United States
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. 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.
Data availability
Data sets are deposited to the GEO Gene Expression Omnibus, accession number GSE77923
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SATB2 induces transcriptional programs in melanoma that lead to metastatic behaviorNCBI Gene Expression Omnibus, GSE77923.
Article and author information
Author details
Funding
Boehringer Ingelheim Fonds
- Maurizio Fazio
Netherlands Organization for Scientific Research (Rubico Fellowship)
- Ellen van Rooijen
Dutch Cancer Foundation
- Ellen van Rooijen
National Cancer Institute (R01 CA103846)
- Leonard I Zon
Melanoma Research Alliance
- Leonard I Zon
Starr Foundation
- Richard M White
- Leonard I Zon
Ellison Foundation
- Leonard I Zon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Zebrafish were maintained under IACUC-approved conditions (Boston Children's Hospital Institutional Animal Care and Use Committee protocol # 20-10-4253R).
Reviewing Editor
- Grant McArthur, Peter MacCallum Cancer Centre, Australia
Publication history
- Received: October 27, 2020
- Accepted: February 1, 2021
- Accepted Manuscript published: February 2, 2021 (version 1)
- Version of Record published: February 12, 2021 (version 2)
Copyright
© 2021, Fazio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance
eLife 10:e64370.
https://doi.org/10.7554/eLife.64370
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