SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance
- Fazio, M., van Rooijen, E., Dang, M., van de Hoek, G., Ablain, J., Mito, J.K., Yang, S., Thomas, A., Michael, J., Fabo, T., Modhurima, R., Pessina, P., Kaufman, C.K., Zhou, Y., White, R.M., Zon, L.I.
- eLIFE 10: (Journal)
- Registered Authors
- van Rooijen, Ellen, White, Richard M., Zhou, Yi, Zon, Leonard I.
- cancer biology, zebrafish
- MeSH Terms
- CRISPR-Cas Systems
- Cell Line, Tumor
- Disease Models, Animal
- Drug Resistance, Neoplasm/genetics*
- Gene Expression Regulation, Neoplastic
- Matrix Attachment Region Binding Proteins/genetics
- Matrix Attachment Region Binding Proteins/metabolism*
- Melanoma/drug therapy
- Neoplasm Invasiveness/genetics*
- Neural Crest/cytology
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 33527896 Full text @ Elife
Fazio, M., van Rooijen, E., Dang, M., van de Hoek, G., Ablain, J., Mito, J.K., Yang, S., Thomas, A., Michael, J., Fabo, T., Modhurima, R., Pessina, P., Kaufman, C.K., Zhou, Y., White, R.M., Zon, L.I. (2021) SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance. eLIFE. 10:.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes