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, Juan Pedro Martinez-Barbera*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)
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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.

Original languageEnglish
Article number1819
Pages (from-to)1-14
JournalNature Communications
Volume8
Issue number1
Early online date28 Nov 2017
DOIs
Publication statusPublished - Nov 2017

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