NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin.
- Katarkar A Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Bottoni G Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Clocchiatti A Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Goruppi S Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Bordignon P Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Lazzaroni F Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Gregnanin I Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella, 13900, Italy.
- Ostano P Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella, 13900, Italy.
- Neel V Department of Dermatology, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Dotto GP Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland. paolo.dotto@unil.ch.
- 2020-10-13
Published in:
- Nature communications. - 2020
Animals
Cancer-Associated Fibroblasts
DNA Damage
Female
Forkhead Box Protein O3
Gene Amplification
Humans
Mice
Mice, SCID
Receptor, Notch1
Skin
Skin Neoplasms
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/s41467-020-18919-2
- PMID 33046701
- Persistent URL
- https://sonar.ch/global/documents/901
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