Inactivation of the Hippo tumor suppressor pathway promotes melanoma

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, Craig J. Ceol, Xaralabos Varelas and Neil J. Ganem ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31399-w

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