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Updated: Nov 19, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance
Maurizio Fazio1,2, Ellen van Rooijen1,2, Michelle Dang1,2
1Howard Hughes Medical Institute, Stem Cell Program and the Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, 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. 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.
Insights
Melanoma progression, invasion, and drug resistance can be driven by transcriptional changes, not just genetic mutations. The regulator SATB2 promotes aggressive melanoma by inducing a neural crest-like state.
Area of Science:
- Cancer Biology
- Melanoma Research
- Epigenetics
Background:
- Genomic analyses reveal limited genetic drivers for melanoma metastasis.
- Melanoma exhibits transcriptional states linked to invasion and drug resistance.
- Zebrafish models with minimal genetic evolution allow study of transcriptional adaptation.
Purpose of the Study:
- To investigate if transcriptional adaptation can drive melanoma progression.
- To identify specific transcriptional regulators involved in melanoma aggressiveness.
- To explore the role of SATB2 in melanoma invasion and drug resistance.
Main Methods:
- Overexpression screen of 80 epigenetic/transcriptional regulators in a zebrafish melanoma model (mitfa:BRAFV600E;tp53-/-).
- Assessment of tumor invasion, invadopodia formation, and drug resistance in zebrafish and human melanoma cell lines.
- Analysis of SATB2 binding targets and induced transcriptional programs, including MITFlowAXLhigh and AQP1+NGFR1high states.
Main Results:
- SATB2 overexpression accelerated aggressive melanoma development in zebrafish.
- SATB2 induced invadopodia formation and invasion in both zebrafish and human melanoma cells.
- SATB2 activated neural crest regulators, driving transcriptional programs associated with drug resistance and enhanced tumor propagation.
- SATB2-induced transcriptional rewiring conferred Vemurafenib resistance in vivo.
Conclusions:
- Transcriptional rewiring, driven by SATB2, can promote melanoma invasion and drug resistance.
- SATB2 facilitates a transition to a neural crest-mesenchyme-like transcriptional state, enhancing melanoma aggressiveness.
- This study highlights the critical role of epigenetic and transcriptional regulation in melanoma progression and therapeutic resistance.
