Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma

Jose Mario Gonzalez-Meljem, Scott Haston, Gabriela Carreno, John R. Apps, Sara Pozzi, Christina Stache, Grace Kaushal, Alex Virasami, Leonidas Panousopoulos, Seyedeh Neda Mousavy-Gharavy, Ana Guerrero, Mamunur Rashid, Nital Jani, Colin R. Goding, Thomas S. Jacques, David J. Adams, Jesus Gil, Cynthia L. Andoniadou and Juan Pedro Martinez-Barbera ()
Additional contact information
Jose Mario Gonzalez-Meljem: Birth Defects Research Centre, UCL Institute of Child Health
Scott Haston: Birth Defects Research Centre, UCL Institute of Child Health
Gabriela Carreno: Birth Defects Research Centre, UCL Institute of Child Health
John R. Apps: Birth Defects Research Centre, UCL Institute of Child Health
Sara Pozzi: Birth Defects Research Centre, UCL Institute of Child Health
Christina Stache: Birth Defects Research Centre, UCL Institute of Child Health
Grace Kaushal: Birth Defects Research Centre, UCL Institute of Child Health
Alex Virasami: Great Ormond Street Hospital for Children
Leonidas Panousopoulos: Birth Defects Research Centre, UCL Institute of Child Health
Seyedeh Neda Mousavy-Gharavy: Birth Defects Research Centre, UCL Institute of Child Health
Ana Guerrero: Imperial College London, Hammersmith Campus, Du Cane Road
Mamunur Rashid: Wellcome Trust Sanger Institute, Hinxton
Nital Jani: UCL Institute of Child Health
Colin R. Goding: Oxford University, Old Road Campus, Headington
Thomas S. Jacques: Birth Defects Research Centre, UCL Institute of Child Health
David J. Adams: Wellcome Trust Sanger Institute, Hinxton
Jesus Gil: Imperial College London, Hammersmith Campus, Du Cane Road
Cynthia L. Andoniadou: King’s College London, Guy’s Hospital, Floor 27 Tower Wing
Juan Pedro Martinez-Barbera: Birth Defects Research Centre, UCL Institute of Child Health

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2− cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.

Date: 2017
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DOI: 10.1038/s41467-017-01992-5

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