SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice.
P27, a cell cycle inhibitor, is also able to drive repression of Sox2 This interaction plays a crucial role during development of p27  pituitary tumors because loss of one copy of Sox2 impairs tumorigenesis [H. Li et al., Cell Stem Cell 11, 845-852 (2012)]. However, SOX2 is expressed in both endocrine and stem cells (SCs), and its contribution to tumorigenesis in either cell type is unknown. We have thus explored the cellular origin and mechanisms underlying endocrine tumorigenesis in p27  pituitaries. We found that pituitary hyperplasia is associated with reduced cellular differentiation, in parallel with increased levels of SOX2 in stem and endocrine cells. Using conditional loss-of-function and lineage tracing approaches, we show that SOX2 is required cell autonomously in p27  endocrine cells for these to give rise to tumors, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), the target of P27 repressive action. Single cell transcriptomic analysis further reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for tumorigenesis. Altogether, our data highlight different aspects of the role of SOX2 following loss of p27, according to cellular context, and uncover an unexpected SOX2-dependent tumor-promoting role for SCs. Our results imply that targeting SCs, in addition to tumor cells, may represent an efficient antitumoral strategy in certain contexts.
['Moncho-Amor|Veronica|V|', 'Chakravarty|Probir|P|', 'Galichet|Christophe|C|0000-0003-0244-9381', 'Matheu|Ander|A|', 'Lovell-Badge|Robin|R|0000-0001-9364-4179', 'Rizzoti|Karine|K|0000-0003-0711-5452']
D000818:Animals D063646:Carcinogenesis D019070:Cell Lineage D050760:Cyclin-Dependent Kinase Inhibitor p27 D055098:Endocrine Cells D000073658:Loss of Function Mutation D020935:MAP Kinase Signaling System D051379:Mice D008810:Mice, Inbred C57BL D014411:Neoplastic Stem Cells D010911:Pituitary Neoplasms D000072417:Protein Domains D055748:SOXB1 Transcription Factors
pituitary tumorigenesis stem cell