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

Athena Georgilis, Sabrina Klotz, Christopher J. Hanley, Nicolas Herranz, Benedikt Weirich, Beatriz Morancho, Ana Carolina Leote, Luana D'Artista, Suchira Gallage, Marco Seehawer, Thomas Carroll, Gopuraja Dharmalingam, Keng Boon Wee, Marco Mellone, Joaquim Pombo, Danijela Heide, Ernesto Guccione, Joaquín Arribas, Nuno L. Barbosa-Morais, Mathias HeikenwalderGareth J. Thomas, Lars Zender, Jesús Gil

    Research output: Contribution to journalArticleResearchpeer-review

    46 Citations (Scopus)

    Abstract

    © 2018 The Authors 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.
    Original languageEnglish
    Pages (from-to)85-102.e9
    JournalCancer Cell
    Volume34
    Issue number1
    DOIs
    Publication statusPublished - 9 Jul 2018

    Keywords

    • EXOC7
    • Oncogene-induced senescence
    • PTBP1
    • RNAi screen
    • SASP
    • alternative splicing
    • senescence

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