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

作者：Mario Gonzalez Meljem Jose; Haston Scott; Carreno Gabriela; Apps John R; Pozzi Sara; Stache Christina; Kaushal Grace; Virasami Alex; Panousopoulos Leonidas; Mousavy Gharavy Seyedeh Neda; Guerrero Ana; Rashid Mamunur; Jani Nital; Goding Colin R; Jacques Thomas S; Adams David J; Gil Jesus; Andoniadou Cynthia L; Martinez Barbera Juan Pedro^*

来源：Nature Communications, 2017, 8(1): 1819.

DOI：10.1038/s41467-017-01992-5

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 beta-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 beta-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.

• 出版日期2017-11-28