NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 10 2020
12 10 2020
Historique:
received:
07
09
2019
accepted:
09
09
2020
entrez:
13
10
2020
pubmed:
14
10
2020
medline:
5
11
2020
Statut:
epublish
Résumé
Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment. Genomic alterations in these cells remain a point of contention. We report that CAFs from skin squamous cell carcinomas (SCCs) display chromosomal alterations, with heterogeneous NOTCH1 gene amplification and overexpression that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 amplification is expanded by chronic UVA exposure, to which CAFs are resistant. The advantage conferred by NOTCH1 amplification and overexpression can be explained by NOTCH1 ability to block the DNA damage response (DDR) and ensuing growth arrest through suppression of ATM-FOXO3a association and downstream signaling cascade. In an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer/stromal cells expansion. Here we show that NOTCH1 gene amplification and increased expression in CAFs are an attractive target for stroma-focused anti-cancer intervention.
Identifiants
pubmed: 33046701
doi: 10.1038/s41467-020-18919-2
pii: 10.1038/s41467-020-18919-2
pmc: PMC7550609
doi:
Substances chimiques
FOXO3 protein, human
0
Forkhead Box Protein O3
0
NOTCH1 protein, human
0
Notch1 protein, mouse
0
Receptor, Notch1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5126Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR039190
Pays : United States
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