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

Mitsuteru Natsuizaka; Kelly A. Whelan; Shingo Kagawa; Kohji Tanakaya; Veronique Giroux; P. M. Chandramouleeswaran; A. Long; Varun Sahu; D. S. Darling; Jianwen Que; Yizeng Yang; Jonathan P. Katz; EP Wileyto; Devraj Basu; Y. Kita; S. Natsugoe; Seiji Naganuma; Andrés J.P. Klein-Szanto; J. Alan Diehl; Adam J. Bass; Kwok Kin Wong; AK Rustgi; Hiroshi Nakagawa

doi:10.1038/s41467-017-01500-9

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

Mitsuteru Natsuizaka
, Kelly A. Whelan
, Shingo Kagawa
, Kohji Tanakaya
, Veronique Giroux
, P. M. Chandramouleeswaran
, A. Long
, Varun Sahu
, D. S. Darling
, Jianwen Que
, Yizeng Yang
, Jonathan P. Katz
, EP Wileyto
, Devraj Basu
, Y. Kita
, S. Natsugoe
, Seiji Naganuma
, Andrés J.P. Klein-Szanto
, J. Alan Diehl
, Adam J. Bass

Kwok Kin Wong, AK Rustgi, Hiroshi Nakagawa

Cancer Signaling and Microenvironment (CSM)

Research output: Contribution to journal › Article › peer-review

173 Scopus citations

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.

Original language	English
Article number	1758
Pages (from-to)	1758
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01500-9
State	Published - Dec 1 2017

Keywords

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

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10.1038/s41467-017-01500-9

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Natsuizaka, M., Whelan, K. A., Kagawa, S., Tanakaya, K., Giroux, V., Chandramouleeswaran, P. M., Long, A., Sahu, V., Darling, D. S., Que, J., Yang, Y., Katz, J. P., Wileyto, EP., Basu, D., Kita, Y., Natsugoe, S., Naganuma, S., Klein-Szanto, A. J. P., Diehl, J. A., ... Nakagawa, H. (2017). Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nature Communications, 8(1), 1758. Article 1758. https://doi.org/10.1038/s41467-017-01500-9

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title = "Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma",

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.",

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

author = "Mitsuteru Natsuizaka and Whelan, \{Kelly A.\} and Shingo Kagawa and Kohji Tanakaya and Veronique Giroux and Chandramouleeswaran, \{P. M.\} and A. Long and Varun Sahu and Darling, \{D. S.\} and Jianwen Que and Yizeng Yang and Katz, \{Jonathan P.\} and EP Wileyto and Devraj Basu and Y. Kita and S. Natsugoe and Seiji Naganuma and Klein-Szanto, \{Andr{\'e}s J.P.\} and Diehl, \{J. Alan\} and Bass, \{Adam J.\} and Wong, \{Kwok Kin\} and AK Rustgi and Hiroshi Nakagawa",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-01500-9",

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Natsuizaka, M, Whelan, KA, Kagawa, S, Tanakaya, K, Giroux, V, Chandramouleeswaran, PM, Long, A, Sahu, V, Darling, DS, Que, J, Yang, Y, Katz, JP, Wileyto, EP, Basu, D, Kita, Y, Natsugoe, S, Naganuma, S, Klein-Szanto, AJP, Diehl, JA, Bass, AJ, Wong, KK, Rustgi, AK & Nakagawa, H 2017, 'Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma', Nature Communications, vol. 8, no. 1, 1758, pp. 1758. https://doi.org/10.1038/s41467-017-01500-9

TY - JOUR

T1 - Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

AU - Natsuizaka, Mitsuteru

AU - Whelan, Kelly A.

AU - Kagawa, Shingo

AU - Tanakaya, Kohji

AU - Giroux, Veronique

AU - Chandramouleeswaran, P. M.

AU - Long, A.

AU - Sahu, Varun

AU - Darling, D. S.

AU - Que, Jianwen

AU - Yang, Yizeng

AU - Katz, Jonathan P.

AU - Wileyto, EP

AU - Basu, Devraj

AU - Kita, Y.

AU - Natsugoe, S.

AU - Naganuma, Seiji

AU - Klein-Szanto, Andrés J.P.

AU - Diehl, J. Alan

AU - Bass, Adam J.

AU - Wong, Kwok Kin

AU - Rustgi, AK

AU - Nakagawa, Hiroshi

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinogenesis

KW - Carcinoma, Squamous Cell/genetics

KW - Cell Line, Tumor

KW - Epithelial-Mesenchymal Transition

KW - Esophageal Squamous Cell Carcinoma/genetics

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Hyaluronan Receptors/genetics

KW - Mice

KW - Mice, Nude

KW - Mice, Transgenic

KW - Receptor, Notch1/genetics

KW - Receptor, Notch3/genetics

KW - Transforming Growth Factor beta/genetics

KW - Tumor Microenvironment

KW - Zinc Finger E-box-Binding Homeobox 1/genetics

UR - https://www.scopus.com/pages/publications/85034987097

U2 - 10.1038/s41467-017-01500-9

DO - 10.1038/s41467-017-01500-9

M3 - Article

C2 - 29170450

SN - 2041-1723

VL - 8

SP - 1758

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1758

ER -

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

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Keywords

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