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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
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,Rustdoi
10.1038/s41467-017-01500-9subject
Has Abstractpub_date
2017-11-24 00:00:00pages
1758issue
1issn
2041-1723pii
10.1038/s41467-017-01500-9journal_volume
8pub_type
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