Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

  1. Emily J Lodge
  2. Alice Santambrogio
  3. John P Russell
  4. Paraskevi Xekouki
  5. Thomas S Jacques
  6. Randy L Johnson
  7. Selvam Thavaraj
  8. Stefan R Bornstein
  9. Cynthia Lilian Andoniadou  Is a corresponding author
  1. King's College London, United Kingdom
  2. Great Ormond Street Hospital for Children, United Kingdom
  3. The University of Texas, MD Anderson Cancer Center, United States
  4. University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany

Abstract

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Emily J Lodge

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0932-8515
  2. Alice Santambrogio

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. John P Russell

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Paraskevi Xekouki

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas S Jacques

    Department of Histopathology, Great Ormond Street Hospital for Children, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Randy L Johnson

    Department of Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Selvam Thavaraj

    Centre for Oral, Clinical and Translational Sciences, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Stefan R Bornstein

    Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Cynthia Lilian Andoniadou

    Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
    For correspondence
    cynthia.andoniadou@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4311-5855

Funding

Medical Research Council (MR/L016729/1)

  • Cynthia Lilian Andoniadou

Lister Institute of Preventive Medicine (Prize Fellowship 2016)

  • Cynthia Lilian Andoniadou

Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1)

  • Stefan R Bornstein
  • Cynthia Lilian Andoniadou

Guy's and St Thomas' Charity (Prize PhD Programme)

  • Emily J Lodge

Deutsche Forschungsgemeinschaft (GRK 2251)

  • Stefan R Bornstein
  • Cynthia Lilian Andoniadou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance to UK Home Office Regulations and experimental procedures were approved by the King's College Ethical Review Process.

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: November 28, 2018
  2. Accepted: March 25, 2019
  3. Accepted Manuscript published: March 26, 2019 (version 1)
  4. Version of Record published: April 12, 2019 (version 2)

Copyright

© 2019, Lodge 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. Emily J Lodge
  2. Alice Santambrogio
  3. John P Russell
  4. Paraskevi Xekouki
  5. Thomas S Jacques
  6. Randy L Johnson
  7. Selvam Thavaraj
  8. Stefan R Bornstein
  9. Cynthia Lilian Andoniadou
(2019)
Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade
eLife 8:e43996.
https://doi.org/10.7554/eLife.43996

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