Intra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence.

TitleIntra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence.
Publication TypeJournal Article
Year of Publication2022
AuthorsCambuli F, Foletto V, Alaimo A, De Felice D, Gandolfi F, Palumbieri MDilia, Zaffagni M, Genovesi S, Lorenzoni M, Celotti M, Bertossio E, Mazzero G, Bertossi A, Bisio A, Berardinelli F, Antoccia A, Gaspari M, Barbareschi M, Fiorentino M, Shen MM, Loda M, Romanel A, Lunardi A
JournalEMBO Rep
Volume23
Issue5
Paginatione54049
Date Published2022 May 04
ISSN1469-3178
KeywordsActivins, Animals, Male, Mice, Prostate, Signal Transduction, Transforming Growth Factor beta
Abstract

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.

DOI10.15252/embr.202154049
Alternate JournalEMBO Rep
PubMed ID35253958
PubMed Central IDPMC9066067
Grant ListR01 CA238005 / CA / NCI NIH HHS / United States
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