Advertisement

 

 

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

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.
Author Information (click to view)

Natsuizaka M, Whelan KA, Kagawa S, Tanaka 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 AJ, Diehl JA, Bass AJ, Wong KK, Rustgi AK, Nakagawa H,


Natsuizaka M, Whelan KA, Kagawa S, Tanaka 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 AJ, Diehl JA, Bass AJ, Wong KK, Rustgi AK, Nakagawa H, (click to view)

Natsuizaka M, Whelan KA, Kagawa S, Tanaka 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 AJ, Diehl JA, Bass AJ, Wong KK, Rustgi AK, Nakagawa H,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

Nature communications 2017 11 248(1) 1758 doi 10.1038/s41467-017-01500-9

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.

Submit a Comment

Your email address will not be published. Required fields are marked *

fourteen − one =

[ HIDE/SHOW ]