Inactivation of the Hippo tumor suppressor pathway promotes melanoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 29, 2022
- Source ID
- 10.1038/s41467-022-31399-w
Entities
People
- Andrew Tilston-Lunel
- Craig J Ceol
- Deborah Lang
- Eric Xia
- Joshua D Campbell
- Kristyna Kotynkova
- Lee Huang
- Marc A. Vittoria
- Nathan Kingston
- Neil J Ganem
- Revati Darp
- Rui Hong
- Shayna Mcdonald
- Xaralabos Varelas
- Xiaowei Xu
Organizations
- American Cancer Society
- Harry J. Lloyd Charitable Trust
- Melanoma Research Alliance
- National Cancer Institute
- National Heart, Lung, and Blood Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services