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

• Published in: Nature communications Vol. 8; no. 1; pp. 1819 - 14
• Main Authors: Gonzalez-Meljem, Jose Mario, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.11.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/71; 692/4028/67/2332; Age; Aniline Compounds - pharmacology; Animal models; Animals; beta Catenin - metabolism; Biphenyl Compounds - pharmacology; Bone cancer; Brain cancer; Brain tumors; Cell Transformation, Neoplastic; Cellular Senescence - physiology; Child; Clusters; Craniopharyngioma - metabolism; Craniopharyngioma - pathology; Disease Models, Animal; Embryos; Exome Sequencing; Genetic transformation; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Neoplasia; Neoplastic Stem Cells - metabolism; Nitrophenols - pharmacology; Oncogenes - physiology; Paracrine signalling; Piperazines - pharmacology; Pituitary; Pituitary gland; Pituitary Gland - metabolism; Pituitary Gland - pathology; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - pathology; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Senescence; SOXB1 Transcription Factors - metabolism; Stem cell transplantation; Stem cells; Sulfonamides - pharmacology; Tumorigenesis; Tumors; Young Adult; β-Catenin
• ISSN: 2041-1723; 2041-1723
• 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 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. Senescent cells can promote tumour progression through the activation of a senescenceassociated secretory phenotype (SASP). Here, the authors show that SASP activation is associated with non-cell autonomous cell transformation and tumour initiation in an in vivo model of adamantinomatous craniopharyngioma.