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Inactivation of the Hippo tumor suppressor pathway promotes melanoma

Author

Listed:
  • Marc A. Vittoria

    (Boston University School of Medicine)

  • Nathan Kingston

    (Boston University School of Medicine)

  • Kristyna Kotynkova

    (Boston University School of Medicine)

  • Eric Xia

    (Boston University School of Medicine)

  • Rui Hong

    (Boston University School of Medicine)

  • Lee Huang

    (Boston University School of Medicine)

  • Shayna McDonald

    (Boston University School of Medicine)

  • Andrew Tilston-Lunel

    (Boston University School of Medicine)

  • Revati Darp

    (University of Massachusetts Medical School)

  • Joshua D. Campbell

    (Boston University School of Medicine)

  • Deborah Lang

    (Boston University School of Medicine)

  • Xiaowei Xu

    (University of Pennsylvania Perelman School of Medicine)

  • Craig J. Ceol

    (University of Massachusetts Medical School)

  • Xaralabos Varelas

    (Boston University School of Medicine)

  • Neil J. Ganem

    (Boston University School of Medicine
    Boston University School of Medicine)

Abstract

Melanoma is commonly driven by activating mutations in the MAP kinase BRAF; however, oncogenic BRAF alone is insufficient to promote melanomagenesis. Instead, its expression induces a transient proliferative burst that ultimately ceases with the development of benign nevi comprised of growth-arrested melanocytes. The tumor suppressive mechanisms that restrain nevus melanocyte proliferation remain poorly understood. Here we utilize cell and murine models to demonstrate that oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway, both in melanocytes in vitro and nevus melanocytes in vivo. Mechanistically, we show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. We also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas. Our data reveal that the Hippo pathway enforces the stable arrest of nevus melanocytes and represents a critical barrier to melanoma development.

Suggested Citation

  • Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31399-w
    DOI: 10.1038/s41467-022-31399-w
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    1. Chrysiis Michaloglou & Liesbeth C. W. Vredeveld & Maria S. Soengas & Christophe Denoyelle & Thomas Kuilman & Chantal M. A. M. van der Horst & Donné M. Majoor & Jerry W. Shay & Wolter J. Mooi & Daniel , 2005. "BRAFE600-associated senescence-like cell cycle arrest of human naevi," Nature, Nature, vol. 436(7051), pages 720-724, August.
    2. Amaya Viros & Berta Sanchez-Laorden & Malin Pedersen & Simon J. Furney & Joel Rae & Kate Hogan & Sarah Ejiama & Maria Romina Girotti & Martin Cook & Nathalie Dhomen & Richard Marais, 2014. "Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53," Nature, Nature, vol. 511(7510), pages 478-482, July.
    3. Ryan J. Quinton & Amanda DiDomizio & Marc A. Vittoria & Kristýna Kotýnková & Carlos J. Ticas & Sheena Patel & Yusuke Koga & Jasmine Vakhshoorzadeh & Nicole Hermance & Taruho S. Kuroda & Neha Parulekar, 2021. "Whole-genome doubling confers unique genetic vulnerabilities on tumour cells," Nature, Nature, vol. 590(7846), pages 492-497, February.
    4. Annelien Verfaillie & Hana Imrichova & Zeynep Kalender Atak & Michael Dewaele & Florian Rambow & Gert Hulselmans & Valerie Christiaens & Dmitry Svetlichnyy & Flavie Luciani & Laura Van den Mooter & So, 2015. "Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state," Nature Communications, Nature, vol. 6(1), pages 1-16, May.
    5. Nathaniel Kastan & Ksenia Gnedeva & Theresa Alisch & Aleksandra A. Petelski & David J. Huggins & Jeanne Chiaravalli & Alla Aharanov & Avraham Shakked & Eldad Tzahor & Aaron Nagiel & Neil Segil & A. J., 2021. "Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Ismael A. Vergara & Christopher P. Mintoff & Shahneen Sandhu & Lachlan McIntosh & Richard J. Young & Stephen Q. Wong & Andrew Colebatch & Daniel L. Cameron & Julia Lai Kwon & Rory Wolfe & Angela Peng , 2021. "Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Raffaella Di Micco & Marzia Fumagalli & Angelo Cicalese & Sara Piccinin & Patrizia Gasparini & Chiara Luise & Catherine Schurra & Massimiliano Garre’ & Paolo Giovanni Nuciforo & Aaron Bensimon & Rober, 2006. "Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication," Nature, Nature, vol. 444(7119), pages 638-642, November.
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