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Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation

Author

Listed:
  • Soumitra Ghosh

    (Centre Hospitalier Universitaire Vaudois
    University of Lausanne
    Birla Institute of Technology and Science (BITS) Pilani Campus)

  • Jovan Isma

    (University of Lausanne
    Massachusetts General Hospital and Harvard Medical School)

  • Paola Ostano

    (Edo and Elvo Tempia Valenta Foundation)

  • Luigi Mazzeo

    (University of Lausanne)

  • Annagiada Toniolo

    (University of Lausanne)

  • Monalisa Das

    (University of Lausanne)

  • Joni R. White

    (Massachusetts General Hospital and Harvard Medical School)

  • Christian Simon

    (Centre Hospitalier Universitaire Vaudois
    International Cancer Prevention Institute)

  • G. Paolo Dotto

    (Centre Hospitalier Universitaire Vaudois
    University of Lausanne
    Massachusetts General Hospital and Harvard Medical School
    International Cancer Prevention Institute)

Abstract

Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR activity. AR associates with nuclear lamin A/C, and its loss causes lamin A/C nucleoplasmic redistribution. AR serves as a bridge between lamin A/C and the protein phosphatase PPP1. Loss of AR decreases lamin-PPP1 association and increases lamin A/C phosphorylation at Ser 301, a characteristic of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the regulatory region of CAF effector genes of the myofibroblast subtype. Expression of a lamin A/C Ser301 phosphomimetic mutant alone can transform normal fibroblasts into tumor-promoting CAFs.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52344-z
    DOI: 10.1038/s41467-024-52344-z
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    1. Hong Sheng Quah & Elaine Yiqun Cao & Lisda Suteja & Constance H. Li & Hui Sun Leong & Fui Teen Chong & Shilpi Gupta & Camille Arcinas & John F. Ouyang & Vivian Ang & Teja Celhar & Yunqian Zhao & Hui C, 2023. "Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
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