Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression.
Fiche publication
Date publication
juillet 2022
Journal
Science advances
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LINDNER Véronique, Dr METZGER Daniel, Pr NAMER Izzie-Jacques, Dr LAVERNY Gilles
Tous les auteurs :
Abu El Maaty MA, Terzic J, Keime C, Rovito D, Lutzing R, Yanushko D, Parisotto M, Grelet E, Namer IJ, Lindner V, Laverny G, Metzger D
Lien Pubmed
Résumé
Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten mice that recapitulate prostate carcinogenesis in humans. We found that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, thus enhancing malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity, leading to the emergence of cells that overexpress Transglutaminase 2 (TGM2) and have impaired androgen signaling. Elevated TGM2 levels in patients with PCa are associated with shortened progression-free survival after prostatectomy. Last, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.
Référence
Sci Adv. 2022 07 22;8(29):eabo2295