TMED9 drives non-small-cell lung cancer progression via promotion of autophagy by recruiting USP5 to deubiquitinate ATG9A
Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine transmembranaire TMED9 favorise la progression d'un cancer du poumon non à petites cellules en recrutant la protéase USP5 pour faciliter la déubiquitination et la stabilisation de la protéine ATG9A et activer l'autophagie puis démontre que l'inhibition de TMED9 sensibilise les cellules cancéreuses à l'osimertinib
Non-small-cell lung cancer (NSCLC), the predominant type of lung cancer, is characterized by high invasiveness and significant mortality. Despite its clinical impact, the molecular mechanisms driving its pathogenesis and progression remain poorly understood. This study demonstrates that TMED9 is overexpressed in NSCLC and showed using multiple independent sample sets that its expression level is significantly associated with poor patient prognosis. Gain- and loss-of-function experiments revealed that TMED9 promotes proliferation, invasion, and migration of NSCLC cells in vitro and significantly accelerates tumor growth and metastasis in vivo. Mechanistically, TMED9 interacts with ATG9A and recruits USP5 to facilitate the deubiquitination and stabilization of ATG9A, thereby activating autophagy and driving malignant progression. Notably, genetic depletion of TMED9 enhances the sensitivity of NSCLC cells to osimertinib. Collectively, these findings identify the TMED9–USP5–ATG9A signaling axis as a critical driver of NSCLC malignancy, highlighting TMED9 as a promising therapeutic target.
Proceedings of the National Academy of Sciences , résumé, 2026