Article Dans Une Revue eLife Année : 2021

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

Maurizio Fazio
Ellen van Rooijen
  • Fonction : Auteur
Michelle Dang
  • Fonction : Auteur
Glenn van de Hoek
  • Fonction : Auteur
Jeffrey K Mito
  • Fonction : Auteur
Song Yang
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Andrew Thomas
  • Fonction : Auteur
Jonathan Michael
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Tania Fabo
Rodsy Modhurima
  • Fonction : Auteur
Patrizia Pessina
  • Fonction : Auteur
Charles K Kaufman
Yi Zhou
  • Fonction : Auteur
Richard M White
Leonard I Zon
  • Fonction : Auteur
  • PersonId : 973559

Résumé

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 MITF low AXL high and AQP1 + NGFR1 high drugresistant 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.

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Cancer
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hal-04942750 , version 1 (12-02-2025)

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Maurizio Fazio, Ellen van Rooijen, Michelle Dang, Glenn van de Hoek, Julien Ablain, et al.. SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance. eLife, 2021, 10, ⟨10.7554/elife.64370⟩. ⟨hal-04942750⟩
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