Sox2 Suppresses Gastric Tumorigenesis in Mice

Abby Sarkar; Aaron J. Huebner; Rita Sulahian; Anthony Anselmo; Xinsen Xu; Kyle Flattery; Niyati Desai; Carlos Sebastian; Mary Anna Yram; Katrin Arnold; Miguel Rivera; Raul Mostoslavsky; Roderick Bronson; Adam J. Bass; Ruslan Sadreyev; Ramesh A. Shivdasani; Konrad Hochedlinger

doi:10.1016/j.celrep.2016.07.034

Cell Reports (Aug 2016)

Sox2 Suppresses Gastric Tumorigenesis in Mice

Abby Sarkar,
Aaron J. Huebner,
Rita Sulahian,
Anthony Anselmo,
Xinsen Xu,
Kyle Flattery,
Niyati Desai,
Carlos Sebastian,
Mary Anna Yram,
Katrin Arnold,
Miguel Rivera,
Raul Mostoslavsky,
Roderick Bronson,
Adam J. Bass,
Ruslan Sadreyev,
Ramesh A. Shivdasani,
Konrad Hochedlinger

Affiliations

Abby Sarkar: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Aaron J. Huebner: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Rita Sulahian: Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Anthony Anselmo: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Xinsen Xu: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Kyle Flattery: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Niyati Desai: Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Carlos Sebastian: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Mary Anna Yram: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Katrin Arnold: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Miguel Rivera: Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Raul Mostoslavsky: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Roderick Bronson: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Adam J. Bass: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Ruslan Sadreyev: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Ramesh A. Shivdasani: Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Konrad Hochedlinger: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA

DOI: https://doi.org/10.1016/j.celrep.2016.07.034
Journal volume & issue: Vol. 16, no. 7
pp. 1929 – 1941

Abstract

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Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2+ cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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