OR39-3 The SOX2+ Population of the Adult Murine Pituitary Includes Stem Cells with Paracrine Tumor-Inducing Potential

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR39-Pituitary
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 133 (Moscone Center)
Cynthia Lilian Andoniadou*1, Paul R. Le Tissier1, Larysa Halyna Pevny2, Mehul Tulsidas Dattani3 and Juan Pedro Martinez-Barbera1
1UCL, London, United Kingdom, 2University of North Carolina, Chapel Hill, 3UCL Institute of Child Health, London, United Kingdom
Background: We previously showed that activation of the canonical WNT pathway in uncommitted embryonic precursors of the murine anterior pituitary leads to tumors resembling adamantinomatous craniopharyngioma, however it remains unknown if targeting pituitary stem cells is causative. SOX2+ pituitary cells can self-renew and terminally differentiate in vitro, but their physiological role in vivo and possible contribution to oncogenesis remain largely unknown.

Methods: We have generated a tamoxifen-inducible Cre strain under the control of Sox2 regulatory elements (Sox2-CreERT2) and used this in combination with the R26-YFP reporter to follow the fates of descendants of SOX2+ cells after tamoxifen induction at embryonic and adult stages. In addition, we induced targeted expression of constitutive active β-catenin specifically in SOX2+ stem cells in Sox2CreERT2/+;Ctnnb1lox(ex3)/+;R26YFP/+ mice to determine if activation of the canonical WNT pathway in the SOX2+population leads to tumors.

Results: Using genetic lineage tracing, we show for the first time in vivo, that the SOX2+ cell compartment in both the embryonic and adult pituitary contains long-lived multipotent stem cells able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we demonstrate that the targeted expression of constitutive active β-catenin specifically in SOX2+stem cells gives rise to non-functioning pituitary tumors. Unexpectedly, the tumor mass is not derived from the mutation-sustaining cells, as revealed by lineage tracing. Instead, mutation-sustaining cells express secreted factors such as BMPs, FGFs and SHH, which can stimulate proliferation.

Conclusions: We uncover a novel mechanism by which SOX2+ stem cells initiate pituitary oncogenesis in a paracrine manner as well as provide in vivo evidence for the contribution of SOX2+ cells in the long-term physiological cell turnover of the adult pituitary.

Nothing to Disclose: CLA, PRL, LHP, MTD, JPM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm