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Nat Commun. 2017 Nov 24;8(1):1758. doi: 10.1038/s41467-017-01500-9.

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.

Author information

1
Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
2
Abramson Cancer Center, Philadelphia, PA, 19104, USA.
3
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
4
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, 060-8638, Japan.
5
Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, 260-0856, Japan.
6
Department of Surgery, Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
7
Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Department of Oral Immunology and Infectious Diseases, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, 40202, USA.
9
Department of Medicine, Division of Digestive and Liver Diseases, Columbia University, New York, NY, 10032, USA.
10
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
11
Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan.
12
Department of Pathology, Kochi Medical School, Nankoku-shi, Kochi, 783-8505, Japan.
13
Histopathology Facility and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
14
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
15
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA.
16
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. kwok-kin.wong@nyumc.org.
17
Division of Hematology and Medical Oncology, New York University, New York, NY, 10016, USA. kwok-kin.wong@nyumc.org.
18
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. nakagawh@mail.med.upenn.edu.

Abstract

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

PMID:
29170450
PMCID:
PMC5700926
DOI:
10.1038/s41467-017-01500-9
[Indexed for MEDLINE]
Free PMC Article

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