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

Atul Katarkar, Giulia Bottoni, Andrea Clocchiatti, Sandro Goruppi, Pino Bordignon, Francesca Lazzaroni, Ilaria Gregnanin, Paola Ostano, Victor Neel and G. Paolo Dotto ()
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Atul Katarkar: University of Lausanne
Giulia Bottoni: Massachusetts General Hospital
Andrea Clocchiatti: Massachusetts General Hospital
Sandro Goruppi: Massachusetts General Hospital
Pino Bordignon: University of Lausanne
Francesca Lazzaroni: University of Lausanne
Ilaria Gregnanin: Edo and Elvo Tempia Valenta Foundation
Paola Ostano: Edo and Elvo Tempia Valenta Foundation
Victor Neel: Massachusetts General Hospital
G. Paolo Dotto: University of Lausanne

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18919-2

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