NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

• Published in: Nature communications Vol. 11; no. 1; pp. 1 - 14
• Main Authors: Katarkar, Atul, Bottoni, Giulia, Clocchiatti, Andrea, Goruppi, Sandro, Bordignon, Pino, Lazzaroni, Francesca, Gregnanin, Ilaria, Ostano, Paola, Neel, Victor, Dotto, G. Paolo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-10-2020; Nature Portfolio
• Subjects: 13/106; 38/22; 38/32; 631/67/1813/1352; 631/67/327; 96/2; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18919-2

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.
The presence of genomic alterations in cancer associated fibroblasts (CAFs) is largely unexplored. The authors show that frequent
NOTCH1
gene amplification and overexpression render CAFs resistant to the UVA-induced DNA damage response (DDR) and promote cancer/stromal cells expansion, which can be reversed by NOTCH inhibition.