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1.
Nat Commun ; 8(1): 1819, 2017 11 28.
Article in English | MEDLINE | ID: mdl-29180744

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 ß-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 ß-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.


Subject(s)
Cellular Senescence/physiology , Craniopharyngioma/metabolism , Neoplastic Stem Cells/metabolism , Pituitary Neoplasms/metabolism , Aniline Compounds/pharmacology , Animals , Biphenyl Compounds/pharmacology , Cell Transformation, Neoplastic , Child , Craniopharyngioma/pathology , Disease Models, Animal , Homeodomain Proteins/metabolism , Humans , Mice , Nitrophenols/pharmacology , Oncogenes/physiology , Piperazines/pharmacology , Pituitary Gland/metabolism , Pituitary Gland/pathology , Pituitary Neoplasms/pathology , Repressor Proteins/metabolism , SOXB1 Transcription Factors/metabolism , Sulfonamides/pharmacology , Exome Sequencing , Young Adult , beta Catenin/metabolism
2.
Proc Natl Acad Sci U S A ; 113(5): E548-57, 2016 Feb 02.
Article in English | MEDLINE | ID: mdl-26764381

ABSTRACT

Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/ß-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with ß-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.


Subject(s)
Hypothalamo-Hypophyseal System , Transcription Factor 7-Like 1 Protein/physiology , Animals , Cohort Studies , Humans , Mice , Pituitary Gland/abnormalities , Pituitary Gland/metabolism , Pituitary Gland/physiopathology , Prosencephalon/abnormalities , Prosencephalon/metabolism
3.
Cell Stem Cell ; 13(4): 433-45, 2013 Oct 03.
Article in English | MEDLINE | ID: mdl-24094324

ABSTRACT

Sox2(+) adult mouse pituitary cells can self-renew and terminally differentiate in vitro, but their physiological role in vivo and possible contribution to oncogenesis remain largely unknown. Using genetic lineage tracing, we show here that the Sox2(+) cell compartment of both the embryonic and adult pituitary contains stem/progenitor cells that are able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we show that targeted expression of oncogenic ß-catenin in Sox2(+) cells gives rise to pituitary tumors, but, unexpectedly, the tumor mass is not derived from the Sox2(+) mutation-sustaining cells, suggesting a paracrine role of Sox2(+) cells in pituitary oncogenesis. Our data therefore provide in vivo evidence of a role for Sox2(+) stem/progenitor cells in long-term physiological maintenance of the adult pituitary, and highlight an unexpected non-cell-autonomous role for these cells in the induction of pituitary tumors.


Subject(s)
Homeostasis , Pituitary Gland/cytology , Pituitary Neoplasms/pathology , SOXB1 Transcription Factors/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Animals , Cells, Cultured , Mice , Mice, Transgenic , Mutation , Pituitary Gland/metabolism , Pituitary Neoplasms/metabolism , SOXB1 Transcription Factors/genetics
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