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

Nat Commun. 2017 Nov 28;8(1):1819. doi: 10.1038/s41467-017-01992-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Biphenyl Compounds / pharmacology
  • Cell Transformation, Neoplastic
  • Cellular Senescence / physiology*
  • Child
  • Craniopharyngioma / metabolism*
  • Craniopharyngioma / pathology
  • Disease Models, Animal
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Nitrophenols / pharmacology
  • Oncogenes / physiology
  • Piperazines / pharmacology
  • Pituitary Gland / metabolism
  • Pituitary Gland / pathology
  • Pituitary Neoplasms / metabolism*
  • Pituitary Neoplasms / pathology
  • Repressor Proteins / metabolism
  • SOXB1 Transcription Factors / metabolism
  • Sulfonamides / pharmacology
  • Whole Exome Sequencing
  • Young Adult
  • beta Catenin / metabolism

Substances

  • ABT-737
  • Aniline Compounds
  • Biphenyl Compounds
  • CTNNB1 protein, mouse
  • Hesx1 protein, mouse
  • Homeodomain Proteins
  • Nitrophenols
  • Piperazines
  • Repressor Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Sulfonamides
  • beta Catenin
  • navitoclax