期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-017-01992-5
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资金
- Medical Research Council (MRC) [MR/M000125/1, MR/L016729/1]
- Great Ormond Street Hospital for Children Charity/Children with Cancer UK (GOSHCC/CWCUK) [W1055]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London
- CONACYT-UCL Postgraduate Fellowship
- CONACYT-REDESD travel fellowship
- Wellcome Trust Ph.D. Fellowship
- Cancer Research UK Clinical Research Training Fellowship
- Cancer Research UK
- Wellcome Trust
- ERC Synergy Programme
- Cancer Research UK [S_1731, 13031] Funding Source: researchfish
- Children with Cancer UK [15-190] Funding Source: researchfish
- Medical Research Council [MC_U120085810, MR/M000125/1, MR/L016729/1] Funding Source: researchfish
- MRC [MC_U120085810, MR/L016729/1, MR/M000125/1] Funding Source: UKRI
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.
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