title: Sox2 Suppresses Gastric Tumorigenesis in Mice.
abstract: 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.
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
authors: Abby
authors: A
authors: Sarkar
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
authors: Aaron J
authors: AJ
authors: Huebner
authors: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Rita
authors: R
authors: Sulahian
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Anthony
authors: A
authors: Anselmo
authors: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Xinsen
authors: X
authors: Xu
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
authors: Kyle
authors: K
authors: Flattery
authors: Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Niyati
authors: N
authors: Desai
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Carlos
authors: C
authors: Sebastian
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
authors: Mary Anna
authors: MA
authors: Yram
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
authors: Katrin
authors: K
authors: Arnold
authors: Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Miguel
authors: M
authors: Rivera
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Raul
authors: R
authors: Mostoslavsky
authors: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors: Roderick
authors: R
authors: Bronson
authors: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Adam J
authors: AJ
authors: Bass
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Ruslan
authors: R
authors: Sadreyev
authors: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Ramesh A
authors: RA
authors: Shivdasani
authors: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA. Electronic address: khochedlinger@mgh.harvard.edu.
authors: Konrad
authors: K
authors: Hochedlinger
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C000613192:adenomatous polyposis coli protein, mouse