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

Author

Listed:
  • Atul Katarkar

    (University of Lausanne)

  • Giulia Bottoni

    (Massachusetts General Hospital
    Harvard Medical School)

  • Andrea Clocchiatti

    (Massachusetts General Hospital
    Harvard Medical School)

  • Sandro Goruppi

    (Massachusetts General Hospital
    Harvard Medical School)

  • 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
    Massachusetts General Hospital
    Harvard Medical School
    International Cancer Prevention Institute)

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.

Suggested Citation

  • Atul Katarkar & Giulia Bottoni & Andrea Clocchiatti & Sandro Goruppi & Pino Bordignon & Francesca Lazzaroni & Ilaria Gregnanin & Paola Ostano & Victor Neel & G. Paolo Dotto, 2020. "NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18919-2
    DOI: 10.1038/s41467-020-18919-2
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    Cited by:

    1. Soumitra Ghosh & Jovan Isma & Paola Ostano & Luigi Mazzeo & Annagiada Toniolo & Monalisa Das & Joni R. White & Christian Simon & G. Paolo Dotto, 2024. "Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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