Sox2 Is Required Independently in Both Stem and Differentiated Cells for Pituitary Tumour Genesis in P27 Null Mice

Tumour development can depend on cell intrinsic dysfunction, but, in some cases, extrinsic factors are important drivers. Here, we have established a genetically tractable model demonstrating that the same gene is relevant both cell-autonomously and non-cell-autonomously for tumorigenesis. P27, a cell cycle inhibitor, is also able to drive repression of the transcription factor Sox2. This interaction plays a crucial role during development of p27(-/-) pituitary tumours because loss of one copy of Sox2 impairs tumorigenesis (1). However, SOX2 is expressed in both endocrine and stem cells (SC), 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 tumours, 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 tumour-promoting role for SCs. Our results imply that targeting SCs, in addition to tumour cells, may represent an efficient anti-tumoral strategy in certain contexts. (1) Li H, et al. (2012) p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation. Cell Stem Cell 11(6):845-852.