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.

Intra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence / Cambuli, F.; Foletto, V.; Alaimo, A.; De Felice, D.; Gandolfi, F.; Palumbieri, M. D.; 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, M. M.; Loda, M.; Romanel, A.; Lunardi, A.. - In: EMBO REPORTS. - ISSN 1469-221X. - ELETTRONICO. - 2022:(2022), pp. e5404901-e5404916. [10.15252/embr.202154049]

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

Cambuli F.;Foletto V.;Alaimo A.;De Felice D.;Gandolfi F.;Palumbieri M. D.;Genovesi S.;Lorenzoni M.;Bertossi A.;Bisio A.;Romanel A.;Lunardi A.
2022

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.
Cambuli, F.; Foletto, V.; Alaimo, A.; De Felice, D.; Gandolfi, F.; Palumbieri, M. D.; 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, M. M.; Loda, M.; Romanel, A.; Lunardi, A.
Intra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence / Cambuli, F.; Foletto, V.; Alaimo, A.; De Felice, D.; Gandolfi, F.; Palumbieri, M. D.; 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, M. M.; Loda, M.; Romanel, A.; Lunardi, A.. - In: EMBO REPORTS. - ISSN 1469-221X. - ELETTRONICO. - 2022:(2022), pp. e5404901-e5404916. [10.15252/embr.202154049]
File in questo prodotto:
File Dimensione Formato  
2022 Cambuli .pdf

accesso aperto

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Creative commons
Dimensione 3.88 MB
Formato Adobe PDF
3.88 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/336373
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact