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

Emily J. Lodge; Alice Santambrogio; John P. Russell; Paraskevi Xekouki; Thomas S. Jacques; Randy L. Johnson; Selvam Thavaraj; Stefan R. Bornstein; Cynthia Lilian Andoniadou

doi:10.7554/eLife.43996

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

Emily J. Lodge, Alice Santambrogio, John P. Russell, Paraskevi Xekouki, Thomas S. Jacques, Randy L. Johnson, Selvam Thavaraj, Stefan R. Bornstein, Cynthia Lilian Andoniadou

Cancer Biology

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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.

Original language	English (US)
Article number	e43996
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.43996
State	Published - Mar 2019

ASJC Scopus subject areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry, Genetics and Molecular Biology

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10.7554/eLife.43996

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@article{4467d15ca532405a9fd366b61a5dee07,

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

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.",

author = "Lodge, {Emily J.} and Alice Santambrogio and Russell, {John P.} and Paraskevi Xekouki and Jacques, {Thomas S.} and Johnson, {Randy L.} and Selvam Thavaraj and Bornstein, {Stefan R.} and Andoniadou, {Cynthia Lilian}",

note = "Funding Information: This study has been supported by grant MR/L016729/1 from the MRC and a Lister Institute Research Prize to CLA, by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 as well as GRK 2251 to CLA and SRB. EJL was supported by the King{\textquoteright}s Bioscience Institute and the Guy{\textquoteright}s and St Thomas{\textquoteright} Charity Prize PhD Programme in Biomedical and Translational Science. JPR was supported by a Dianna Trebble Endowment Fund Dental Institute Studentship. We thank Prof. Jacques Drouin and Prof. Simon Rhodes for TPIT and PIT1 antibodies respectively, and the National Hormone and Peptide Program (Harbor–University of California, Los Angeles Medical Center) for providing some of the hormone antibodies used in this study. We thank Prof. Juan Pedro Martinez-Barbera, Dr Rocio Sancho and Dr Marika Charalambous for discussions and critical reading of the manuscript. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} Lodge et al.",

year = "2019",

month = mar,

doi = "10.7554/eLife.43996",

language = "English (US)",

volume = "8",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

AU - Lodge, Emily J.

AU - Santambrogio, Alice

AU - Russell, John P.

AU - Xekouki, Paraskevi

AU - Jacques, Thomas S.

AU - Johnson, Randy L.

AU - Thavaraj, Selvam

AU - Bornstein, Stefan R.

AU - Andoniadou, Cynthia Lilian

N1 - Funding Information: This study has been supported by grant MR/L016729/1 from the MRC and a Lister Institute Research Prize to CLA, by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 as well as GRK 2251 to CLA and SRB. EJL was supported by the King’s Bioscience Institute and the Guy’s and St Thomas’ Charity Prize PhD Programme in Biomedical and Translational Science. JPR was supported by a Dianna Trebble Endowment Fund Dental Institute Studentship. We thank Prof. Jacques Drouin and Prof. Simon Rhodes for TPIT and PIT1 antibodies respectively, and the National Hormone and Peptide Program (Harbor–University of California, Los Angeles Medical Center) for providing some of the hormone antibodies used in this study. We thank Prof. Juan Pedro Martinez-Barbera, Dr Rocio Sancho and Dr Marika Charalambous for discussions and critical reading of the manuscript. The authors declare no conflict of interest. Publisher Copyright: © Lodge et al.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85064725342&partnerID=8YFLogxK

U2 - 10.7554/eLife.43996

DO - 10.7554/eLife.43996

M3 - Article

C2 - 30912742

AN - SCOPUS:85064725342

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

M1 - e43996

ER -

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

Abstract

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