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

  1. Maurizio Fazio
  2. Ellen van Rooijen
  3. Michelle Dang
  4. Glenn van de Hoek
  5. Julien Ablain
  6. Jeffrey K Mito
  7. Song Yang
  8. Andrew Thomas
  9. Jonathan Michael
  10. Tania Fabo
  11. Rodsy Modhurima
  12. Patrizia Pessina
  13. Charles K Kaufman
  14. Yi Zhou
  15. Richard M White
  16. Leonard I Zon  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Brigham and Women's Hospital, United States
  3. Washington University School of Medicine, United States
  4. 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

The following data sets were generated

Article and author information

Author details

  1. Maurizio Fazio

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0083-6601
  2. Ellen van Rooijen

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  3. Michelle Dang

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  4. Glenn van de Hoek

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  5. Julien Ablain

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  6. Jeffrey K Mito

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  7. Song Yang

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  8. Andrew Thomas

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  9. Jonathan Michael

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  10. Tania Fabo

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8987-0672
  11. Rodsy Modhurima

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  12. Patrizia Pessina

    Stem Cell Program, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  13. Charles K Kaufman

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3122-1677
  14. Yi Zhou

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  15. Richard M White

    Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    Richard M White, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9099-9169
  16. Leonard I Zon

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    For correspondence
    zon@enders.tch.harvard.edu
    Competing interests
    Leonard I Zon, LIZ is a founder and stockholder of Fate Therapeutics Inc., Scholar Rock Inc., Camp4 Therapeutics Inc., Amagma Therapeutics Inc., and a scientific advisor for Stemgent..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0860-926X

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

  1. Grant McArthur, Peter MacCallum Cancer Centre, Australia

Publication history

  1. Received: October 27, 2020
  2. Accepted: February 1, 2021
  3. Accepted Manuscript published: February 2, 2021 (version 1)
  4. 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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  1. Maurizio Fazio
  2. Ellen van Rooijen
  3. Michelle Dang
  4. Glenn van de Hoek
  5. Julien Ablain
  6. Jeffrey K Mito
  7. Song Yang
  8. Andrew Thomas
  9. Jonathan Michael
  10. Tania Fabo
  11. Rodsy Modhurima
  12. Patrizia Pessina
  13. Charles K Kaufman
  14. Yi Zhou
  15. Richard M White
  16. Leonard I Zon
(2021)
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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