IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31399-w.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31399-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31399-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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. 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.
    5. 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.
    6. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Jaskaren Kohli & Chen Ge & Eleni Fitsiou & Miriam Doepner & Simone M. Brandenburg & William J. Faller & Todd W. Ridky & Marco Demaria, 2022. "Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Jean-Philippe Coppé & Christopher K Patil & Francis Rodier & Yu Sun & Denise P Muñoz & Joshua Goldstein & Peter S Nelson & Pierre-Yves Desprez & Judith Campisi, 2008. "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor," PLOS Biology, Public Library of Science, vol. 6(12), pages 1-1, December.
    4. Miles C. Andrews & Junna Oba & Chang-Jiun Wu & Haifeng Zhu & Tatiana Karpinets & Caitlin A. Creasy & Marie-Andrée Forget & Xiaoxing Yu & Xingzhi Song & Xizeng Mao & A. Gordon Robertson & Gabriele Roma, 2022. "Multi-modal molecular programs regulate melanoma cell state," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Ana Portelinha & Mariana Silva Ferreira & Tatiana Erazo & Man Jiang & Zahra Asgari & Elisa Stanchina & Anas Younes & Hans-Guido Wendel, 2023. "Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Ahmed A. Raslan & Tho X. Pham & Jisu Lee & Konstantinos Kontodimas & Andrew Tilston-Lunel & Jillian Schmottlach & Jeongmin Hong & Taha Dinc & Andreea M. Bujor & Nunzia Caporarello & Aude Thiriot & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Sascha Schäuble & Karolin Klement & Shiva Marthandan & Sandra Münch & Ines Heiland & Stefan Schuster & Peter Hemmerich & Stephan Diekmann, 2012. "Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-14, August.
    8. Yukinari Haraoka & Yuki Akieda & Yuri Nagai & Chihiro Mogi & Tohru Ishitani, 2022. "Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Simone Ribero & Daniel Glass & Abraham Aviv & Timothy David Spector & Veronique Bataille, 2015. "Height and Bone Mineral Density Are Associated with Naevus Count Supporting the Importance of Growth in Melanoma Susceptibility," PLOS ONE, Public Library of Science, vol. 10(1), pages 1-11, January.
    10. Rong Xiao & Deshu Xu & Meili Zhang & Zhanghua Chen & Li Cheng & Songjie Du & Mingfei Lu & Tonghai Zhou & Ruoyan Li & Fan Bai & Yue Huang, 2024. "Aneuploid embryonic stem cells drive teratoma metastasis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    11. Birthe Dorgau & Joseph Collin & Agata Rozanska & Darin Zerti & Adrienne Unsworth & Moira Crosier & Rafiqul Hussain & Jonathan Coxhead & Tamil Dhanaseelan & Aara Patel & Jane C. Sowden & David R. FitzP, 2024. "Single-cell analyses reveal transient retinal progenitor cells in the ciliary margin of developing human retina," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Michael F. Emmons & Richard L. Bennett & Alberto Riva & Kanchan Gupta & Larissa Anastasio Da Costa Carvalho & Chao Zhang & Robert Macaulay & Daphne Dupéré-Richér & Bin Fang & Edward Seto & John M. Koo, 2023. "HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Gustavo Medeiros & Raphael Ortiz & Petr Strnad & Andrea Boni & Franziska Moos & Nicole Repina & Ludivine Challet Meylan & Francisca Maurer & Prisca Liberali, 2022. "Multiscale light-sheet organoid imaging framework," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Philip Smith & Thomas Bradley & Lena Morrill Gavarró & Teodora Goranova & Darren P. Ennis & Hasan B. Mirza & Dilrini Silva & Anna M. Piskorz & Carolin M. Sauer & Sarwah Al-Khalidi & Ionut-Gabriel Funi, 2023. "The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    15. Wei Wu & Szymon A. Barwacz & Rahul Bhowmick & Katrine Lundgaard & Marisa M. Gonçalves Dinis & Malgorzata Clausen & Masato T. Kanemaki & Ying Liu, 2023. "Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    16. Guillaume Harmange & Raúl A. Reyes Hueros & Dylan L. Schaff & Benjamin Emert & Michael Saint-Antoine & Laura C. Kim & Zijian Niu & Shivani Nellore & Mitchell E. Fane & Gretchen M. Alicea & Ashani T. W, 2023. "Disrupting cellular memory to overcome drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    17. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    18. Hervé Técher & Diyavarshini Gopaul & Jonathan Heuzé & Nail Bouzalmad & Baptiste Leray & Audrey Vernet & Clément Mettling & Jérôme Moreaux & Philippe Pasero & Yea-Lih Lin, 2024. "MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Sandra Buratta & Lorena Urbanelli & Krizia Sagini & Stefano Giovagnoli & Silvia Caponi & Daniele Fioretto & Nico Mitro & Donatella Caruso & Carla Emiliani, 2017. "Extracellular vesicles released by fibroblasts undergoing H-Ras induced senescence show changes in lipid profile," PLOS ONE, Public Library of Science, vol. 12(11), pages 1-23, November.
    20. Claudia Capparelli & Timothy J. Purwin & McKenna Glasheen & Signe Caksa & Manoela Tiago & Nicole Wilski & Danielle Pomante & Sheera Rosenbaum & Mai Q. Nguyen & Weijia Cai & Janusz Franco-Barraza & Ric, 2022. "Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31399-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.