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Intra‐epithelial non‐canonical Activin A signaling safeguards prostate progenitor quiescence
Author(s) -
Cambuli Francesco,
Foletto Veronica,
Alaimo Alessandro,
De Felice Dario,
Gandolfi Francesco,
Palumbieri Maria Dilia,
Zaffagni Michela,
Genovesi Sacha,
Lorenzoni Marco,
Celotti Martina,
Bertossio Emiliana,
Mazzero Giosuè,
Bertossi Arianna,
Bisio Alessandra,
Berardinelli Francesco,
Antoccia Antonio,
Gaspari Marco,
Barbareschi Mattia,
Fiorentino Michelangelo,
Shen Michael M,
Loda Massimo,
Romanel Alessandro,
Lunardi Andrea
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202154049
Subject(s) - conceptualization , systems biology , library science , biology , computational biology , computer science , artificial intelligence
The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF‐β ligands have been known to induce cytostasis in a variety of epithelia, but the intracellular pathway mediating this signal in the prostate, and its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we find that intra‐epithelial non‐canonical Activin A signaling inhibits cell proliferation in a Smad‐independent manner. Mechanistically, Activin A triggers Tak1 and p38 ΜAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurs upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro are also able to implant with increased frequency into immunocompetent mice. This study demonstrates that non‐canonical Activin A signaling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumor progenitors.