PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells

Altres ajuts: We are grateful to A.J. Innes and members of J.G.'s laboratory for reagents, comments, and other contributions to this project. We thank S. Vernia, J. Ule, and R. Faraway for advice and members of the Proteomics (P. Faull and A. Montoya) and Genomics (L. Game, K. Rekopoulou, and A. Ivan) LMS facilities for help with the proteomics and RNA-seq, respectively. We thank T.-W. Kang and C. Fellmeth for technical support and Life Science Editors for editorial assistance. J.A. is funded by the Breast Cancer Research Foundation (BCRF, grant BCRF-17-008) and Instituto de Salud Carlos III. N.L.B.-M.'s laboratory is supported by EMBO (Installation grant 3057) and Fundação para a Ciência e a Tecnologia, Portugal (FCT Investigator Starting grant IF/00595/2014). M.H. was supported by an ERC consolidator grant (HepatoMetabopath). Core support from MRC (grants MC-A652-5PZ00 and MC_U120085810) funded the research in J.G.'s laboratory.Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer. By performing a genetic screen for regulators of the senescence-associated secretory phenotype (SASP), Georgilis et al. identify PTBP1, which controls SASP by regulating alternative splicing of genes involved in intracellular trafficking such as EXOC7. PTBP1 knockdown blocks the tumor-promoting functions of SASP