SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27 -null mice
Open Access
- 11 February 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (7)
- https://doi.org/10.1073/pnas.2017115118
Abstract
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.Keywords
Funding Information
- Medical Research Council, UK (U1175512772)
- Medical Research Council, UK (U117562207)
- Medical Research Council, UK (U117570590)
- Cancer Research UK (FC001107)
- Medical Research Council, UK (FC001107)
- Wellcome (FC001107)
- Worldwide Cancer Research (13-1270)
This publication has 40 references indexed in Scilit:
- Stem cell fate in cancer growth, progression and therapy resistanceNature Reviews Cancer, 2018
- The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanismsThe Journal of Experimental Medicine, 2018
- The non-canonical functions of p27Kip1in normal and tumor biologyCell Cycle, 2016
- Sox2+ Stem/Progenitor Cells in the Adult Mouse Pituitary Support Organ Homeostasis and Have Tumor-Inducing PotentialCell Stem Cell, 2013
- Adult Pituitary Cell Maintenance: Lineage-Specific Contribution of Self-DuplicationMolecular Endocrinology, 2013
- The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodelingGenes & Development, 2012
- Cell cycle control of pituitary development and diseaseJournal of Molecular Endocrinology, 2008
- A Pituitary Cell-Restricted T Box Factor, Tpit, Activates POMC Transcription in Cooperation with Pitx HomeoproteinsCell, 2001
- A Syndrome of Multiorgan Hyperplasia with Features of Gigantism, Tumorigenesis, and Female Sterility in p27 -Deficient MiceCell, 1996
- Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27Cell, 1996