SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance

eLife

Rodsy Modhurima¹  Jeffrey K Mito²  Jonathan Michael²  Ellen van Rooijen²  Glenn van de Hoek²  Leonard I Zon²  Song Yang³  Richard M White³  Yi Zhou³  Patrizia Pessina³  Andrew Thomas³  Tania Fabo³  Charles K Kaufman³  Michelle Dang³  Maurizio Fazio³  Julien Ablain³ 

[1] Brigham and Women’s Hospital, Department of Pathology, Boston, United States;Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, United States;Howard 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;

关键词: melanoma;    SATB2;    metastasis;    neural crest;    drug resistance;    epigenetics;   

DOI  :  10.7554/eLife.64370

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown