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

Mitsuteru Natsuizaka; Kelly A Whelan; Shingo Kagawa; Koji Tanaka; Veronique Giroux; Prasanna M Chandramouleeswaran; Apple Long; Varun Sahu; Douglas S Darling; Jianwen Que; Yizeng Yang; Jonathan P Katz; E Paul Wileyto; Devraj Basu; Yoshiaki Kita; Shoji Natsugoe; Seiji Naganuma; Andres J Klein-Szanto; J Alan Diehl; Adam J Bass; Kwok-Kin Wong; Anil K Rustgi; Hiroshi Nakagawa

doi:10.1038/s41467-017-01500-9

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

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

Authors

Mitsuteru Natsuizaka^{1

2

3

4}, Kelly A Whelan^{1

2

3}, Shingo Kagawa^{1

2

3

5}, Koji Tanaka^{1

2

3

6}, Veronique Giroux^{1

2

3}, Prasanna M Chandramouleeswaran^{1

2

3}, Apple Long^{1

2

3}, Varun Sahu^{2

3

7}, Douglas S Darling⁸, Jianwen Que⁹, Yizeng Yang^{1

2

3}, Jonathan P Katz^{1

2

3}, E Paul Wileyto^{2

3

10}, Devraj Basu^{2

3

7}, Yoshiaki Kita¹¹, Shoji Natsugoe¹¹, Seiji Naganuma¹², Andres J Klein-Szanto¹³, J Alan Diehl¹⁴, Adam J Bass¹⁵, Kwok-Kin Wong^{16

17}, Anil K Rustgi³, Hiroshi Nakagawa¹⁸

Affiliations

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. [email protected].
¹⁷ Division of Hematology and Medical Oncology, New York University, New York, NY, 10016, USA. [email protected].
¹⁸ University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology
Carcinoma, Squamous Cell / physiopathology
Cell Line, Tumor
Epithelial-Mesenchymal Transition*
Esophageal Squamous Cell Carcinoma / genetics
Esophageal Squamous Cell Carcinoma / metabolism*
Esophageal Squamous Cell Carcinoma / physiopathology
Female
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors / genetics
Hyaluronan Receptors / metabolism
Mice
Mice, Nude
Mice, Transgenic
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism*
Receptor, Notch3 / genetics
Receptor, Notch3 / metabolism*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism
Tumor Microenvironment
Zinc Finger E-box-Binding Homeobox 1 / genetics
Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

Hyaluronan Receptors
NOTCH1 protein, human
NOTCH3 protein, human
Receptor, Notch1
Receptor, Notch3
Transforming Growth Factor beta
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding