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

被引：7

作者：

Cambuli, Francesco ^{[1
,2
,10
]}

Foletto, Veronica ^{[1
]}

Alaimo, Alessandro ^{[1
]}

De Felice, Dario ^{[1
]}

Gandolfi, Francesco ^{[3
]}

Palumbieri, Maria Dilia ^{[1
]}

Zaffagni, Michela ^{[1
]}

Genovesi, Sacha ^{[1
]}

Lorenzoni, Marco ^{[1
]}

Celotti, Martina ^{[1
]}

Bertossio, Emiliana ^{[1
]}

Mazzero, Giosue ^{[4
]}

Bertossi, Arianna ^{[1
]}

Bisio, Alessandra ^{[1
]}

Berardinelli, Francesco ^{[5
,6
]}

Antoccia, Antonio ^{[5
]}

Gaspari, Marco ^{[7
]}

Barbareschi, Mattia ^{[4
]}

Fiorentino, Michelangelo ^{[8
]}

Shen, Michael M. ^{[2
]}

Loda, Massimo ^{[9
]}

Romanel, Alessandro ^{[3
]}

Lunardi, Andrea ^{[1
]}

机构：

[1] Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Armenise Harvard Lab Canc Biol & Genet, Trento, Italy

[2] Columbia Univ, Irving Med Ctr, Herbert Irving Comprehens Canc Ctr, Dept Med Genet & Dev,Urol,Syst Biol, New York, NY 10027 USA

[3] Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Lab Bioinformat & Computat Genom, Trento, Italy

[4] Santa Chiara Hosp APSS, Trento, Italy

[5] Univ Roma Tre, Dept Sci, Rome, Italy

[6] IRCCS Santa Lucia Fdn, Neurogenet & Mol Neurobiol Unit, Lab Neurodev, Rome, Italy

[7] Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy

[8] Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy

[9] Cornell Univ, Dept Pathol & Lab Med, Weill Med Coll, New York, NY USA

[10] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

来源：

EMBO REPORTS | 2022年 / 23卷 / 05期

基金：

欧盟地平线“2020”;

关键词：

Activin A; MAP3K7; organoids; prostate; TGF-beta; TO-LUMINAL DIFFERENTIATION; TGF-BETA; ACCELERATES INITIATION; CANCER; CELLS; IDENTIFICATION; INHIBITOR; PROTEIN; TAK1; MICROENVIRONMENT;

D O I：

10.15252/embr.202154049

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-beta 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 MAPK 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 uitro 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.

引用

页数：16