Endocrine Abstracts

The function of stem cells in the anterior pituitary gland, their role in homeostasis during life and possible involvement in pituitary tumours remain largely unknown. We have previously shown that cells exclusively within the Sox2⁺ compartment of the mouse pituitary have progenitor/stem cell properties in culture where they can self-renew and terminally differentiate. To address if these cells act as stem cells in vivo, we generated an inducible Sox2-CreERT2 mouse line, where we can activate Cre in Sox2-expressing cells upon tamoxifen administration. Using genetic lineage tracing, we find that the Sox2⁺ cell compartment of both the embryonic and adult pituitary contains progenitor/stem cells able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during life. Previously, we demonstrated that the targeted expression of oncogenic β-catenin during embryogenesis, in undifferentiated Rathke’s pouch precursors, leads to anterior pituitary tumours resembling adamantinomatous craniopharyngioma. To verify that stem cells are the specific cell type needing to be targeted for tumours to form, we expressed oncogenic β-catenin in adult Sox2⁺ cells using our inducible model. Confirming this notion, we find that pituitary tumours do form, but unexpectedly, the tumour mass does not carry the oncogenic mutation; genetic lineage tracing reveals that the mutation-sustaining Sox2⁺ stem cells are not the cell-of-origin of the tumours. Investigating the mechanism of tumorigenesis, we demonstrate that Sox2⁺ cells targeted with mutant β-catenin express a host of secreted signalling factors, capable of stimulating proliferation and transformation of surrounding cells in a paracrine fashion. In summary, our data demonstrate that Sox2⁺ cells are progenitor/stem cells in vivo, and in addition, we have revealed a novel paracrine mechanism implicating Sox2⁺ cells as instigators of pituitary oncogenesis. Our results have profound implications in the understanding of craniopharyngioma and other pituitary tumours such as adenoma and could facilitate the development of new therapies.