SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in <i>p27</i>-null mice.

Abstract

P27, a cell cycle inhibitor, is also able to drive repression of <i>Sox2</i> This interaction plays a crucial role during development of <i>p27</i>^<i>-/-</i> pituitary tumors because loss of one copy of <i>Sox2</i> impairs tumorigenesis [H. Li <i>et al.</i>, <i>Cell Stem Cell</i> 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 <i>p27</i>^<i>-/-</i> 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 <i>p27</i>^<i>-/-</i> endocrine cells for these to give rise to tumors, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the <i>Sox2</i> regulatory region 2 (<i>Srr2</i>), 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 <i>p27</i>, 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.