TY - JOUR
T1 - PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells
AU - Georgilis, Athena
AU - Klotz, Sabrina
AU - Hanley, Christopher J.
AU - Herranz, Nicolas
AU - Weirich, Benedikt
AU - Morancho, Beatriz
AU - Leote, Ana Carolina
AU - D'Artista, Luana
AU - Gallage, Suchira
AU - Seehawer, Marco
AU - Carroll, Thomas
AU - Dharmalingam, Gopuraja
AU - Wee, Keng Boon
AU - Mellone, Marco
AU - Pombo, Joaquim
AU - Heide, Danijela
AU - Guccione, Ernesto
AU - Arribas, Joaquín
AU - Barbosa-Morais, Nuno L.
AU - Heikenwalder, Mathias
AU - Thomas, Gareth J.
AU - Zender, Lars
AU - Gil, Jesús
PY - 2018/7/9
Y1 - 2018/7/9
N2 - © 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.
AB - © 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.
KW - EXOC7
KW - Oncogene-induced senescence
KW - PTBP1
KW - RNAi screen
KW - SASP
KW - alternative splicing
KW - senescence
U2 - https://doi.org/10.1016/j.ccell.2018.06.007
DO - https://doi.org/10.1016/j.ccell.2018.06.007
M3 - Article
VL - 34
SP - 85-102.e9
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 1
ER -