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

Soumitra Ghosh (), Jovan Isma, Paola Ostano, Luigi Mazzeo, Annagiada Toniolo, Monalisa Das, Joni R. White, Christian Simon and G. Paolo Dotto ()
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Soumitra Ghosh: Centre Hospitalier Universitaire Vaudois
Jovan Isma: University of Lausanne
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
G. Paolo Dotto: Centre Hospitalier Universitaire Vaudois

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52344-z

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