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 Heikenwalder; Gareth J Thomas; Lars Zender; Jesús Gil

doi:10.1016/j.ccell.2018.06.007

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

Cancer Cell. 2018 Jul 9;34(1):85-102.e9. doi: 10.1016/j.ccell.2018.06.007.

Authors

Athena Georgilis¹, Sabrina Klotz², Christopher J Hanley³, Nicolas Herranz¹, Benedikt Weirich⁴, Beatriz Morancho⁵, Ana Carolina Leote⁶, Luana D'Artista², Suchira Gallage⁷, Marco Seehawer², Thomas Carroll¹, Gopuraja Dharmalingam¹, Keng Boon Wee⁸, Marco Mellone³, Joaquim Pombo¹, Danijela Heide⁴, Ernesto Guccione⁹, Joaquín Arribas¹⁰, Nuno L Barbosa-Morais⁶, Mathias Heikenwalder⁴, Gareth J Thomas³, Lars Zender¹¹, Jesús Gil¹²

Affiliations

¹ MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
² Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen 72076, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen 72076, Germany.
³ Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Somers Building, Southampton SO16 6YD, UK.
⁴ Division of Chronic Inflammation and Cancer, German Cancer Research Centre (DKFZ), Heidelberg 69121, Germany.
⁵ Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, Barcelona 08035, Spain.
⁶ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
⁷ MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Division of Chronic Inflammation and Cancer, German Cancer Research Centre (DKFZ), Heidelberg 69121, Germany.
⁸ Institute of High Performance Computing, A(∗)STAR, 1 Fusionopolis Way, #16-16 Connexis, Singapore 138632, Singapore; Bioinformatics Institute, A(∗)STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
⁹ Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore, Singapore.
¹⁰ Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, Barcelona 08035, Spain; Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Campus de la UAB, Bellaterra 08193, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
¹¹ Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen 72076, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen 72076, Germany; Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹² MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. Electronic address: [email protected].

Abstract

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.

Keywords: EXOC7; Oncogene-induced senescence; PTBP1; RNAi screen; SASP; alternative splicing; senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing
Animals
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Cellular Senescence*
Female
Gene Expression Regulation, Neoplastic
Heterogeneous-Nuclear Ribonucleoproteins / genetics
Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
Humans
Inflammation / genetics
Inflammation / metabolism*
Inflammation / pathology
Inflammation / therapy
MCF-7 Cells
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology
Neoplasms / prevention & control
Paracrine Communication
Phenotype
Polypyrimidine Tract-Binding Protein / genetics
Polypyrimidine Tract-Binding Protein / metabolism*
RNA Interference
Signal Transduction
Tumor Burden
Vesicular Transport Proteins / genetics
Vesicular Transport Proteins / metabolism

Substances

Exoc7 protein, mouse
Heterogeneous-Nuclear Ribonucleoproteins
PTBP1 protein, human
Ptbp1 protein, mouse
Vesicular Transport Proteins
Polypyrimidine Tract-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding