LAUSR

Significance Tumor development can depend on cell intrinsic dysfunction, but, in some cases, extrinsic factors are important drivers. Here, we established a genetically tractable model, demonstrating that the same gene is relevant both cell autonomously and noncell autonomously for tumorigenesis. Deletion of p27, down-regulated in many tumors, predominantly leads to development of murine pituitary tumors. SOX2, transcriptionally derepressed in absence of P27, is important for tumorigenesis in this and other models, but little is known about its interaction. Using loss-of-function and lineage tracing approaches, we establish its regulatory interaction in vivo and show that SOX2 is required independently, both in endocrine and stem cells, to orchestrate tumorigenesis in absence of P27, establishing a powerful model to investigate mechanisms of tumor development. 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.