The University of Southampton
University of Southampton Institutional Repository

PTBP1-Mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells

PTBP1-Mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells
PTBP1-Mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells

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.

alternative splicing, EXOC7, Oncogene-induced senescence, PTBP1, RNAi screen, SASP, senescence
1535-6108
85-102.e9
Georgilis, Athena
f944d176-aa4d-41bb-80d4-ed5aea600d35
Klotz, Sabrina
de7dc8a3-0655-48d3-b8c3-cb4a30700f93
Hanley, Christopher J.
7e2d840d-e724-4389-a362-83741ccdf241
Herranz, Nicolas
f3d8c202-b363-4f83-b696-b2e0d72d8fc9
Weirich, Benedikt
110ac8bb-51a2-4284-89fc-0b61517ae8b4
Morancho, Beatriz
b67b4f53-9b0c-4491-90b6-d2e3abe4e9d1
Leote, Ana Carolina
9c1274d8-a09a-4dfa-94e0-d50fcec2ee83
D'Artista, Luana
56057dc7-ff49-44d6-825a-4874c3a2e591
Gallage, Suchira
a2d8dac5-bdf5-42f8-8120-3e8ab586dc7d
Seehawer, Marco
9ea35b18-f762-4ea8-82b8-12ef49743f2e
Carroll, Thomas
7edffea4-df52-4d9e-9f3e-e0daff5d5e52
Dharmalingam, Gopuraja
2840e176-f848-46bd-aa8b-c283f2ff21a2
Wee, Keng Boon
69a04641-ff92-42d5-aef7-1610190d6afa
Mellone, Marco
b0301b32-14f8-4203-9026-b7f90885cab9
Pombo, Joaquim
2d696647-7725-472d-9c66-aae9b591a450
Heide, Danijela
1c22d49d-f8fb-4bd9-a715-6a69fe2d51ce
Guccione, Ernesto
9c537e57-3114-40c9-850c-10d47a8f09bb
Arribas, Joaquín
51ceec1d-3583-40e6-85f3-ba968fac17d1
Barbosa-Morais, Nuno L.
60657d45-26b1-4242-a3a0-adf8eaa6d90c
Heikenwalder, Mathias
c3ade56c-6aa9-4acf-a06b-1c6227175247
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Zender, Lars
2918edd0-368a-4152-8d3c-1689e9b591c6
Gil, Jesús
c5cf7797-79f2-4e17-b714-eefb79214181
Georgilis, Athena
f944d176-aa4d-41bb-80d4-ed5aea600d35
Klotz, Sabrina
de7dc8a3-0655-48d3-b8c3-cb4a30700f93
Hanley, Christopher J.
7e2d840d-e724-4389-a362-83741ccdf241
Herranz, Nicolas
f3d8c202-b363-4f83-b696-b2e0d72d8fc9
Weirich, Benedikt
110ac8bb-51a2-4284-89fc-0b61517ae8b4
Morancho, Beatriz
b67b4f53-9b0c-4491-90b6-d2e3abe4e9d1
Leote, Ana Carolina
9c1274d8-a09a-4dfa-94e0-d50fcec2ee83
D'Artista, Luana
56057dc7-ff49-44d6-825a-4874c3a2e591
Gallage, Suchira
a2d8dac5-bdf5-42f8-8120-3e8ab586dc7d
Seehawer, Marco
9ea35b18-f762-4ea8-82b8-12ef49743f2e
Carroll, Thomas
7edffea4-df52-4d9e-9f3e-e0daff5d5e52
Dharmalingam, Gopuraja
2840e176-f848-46bd-aa8b-c283f2ff21a2
Wee, Keng Boon
69a04641-ff92-42d5-aef7-1610190d6afa
Mellone, Marco
b0301b32-14f8-4203-9026-b7f90885cab9
Pombo, Joaquim
2d696647-7725-472d-9c66-aae9b591a450
Heide, Danijela
1c22d49d-f8fb-4bd9-a715-6a69fe2d51ce
Guccione, Ernesto
9c537e57-3114-40c9-850c-10d47a8f09bb
Arribas, Joaquín
51ceec1d-3583-40e6-85f3-ba968fac17d1
Barbosa-Morais, Nuno L.
60657d45-26b1-4242-a3a0-adf8eaa6d90c
Heikenwalder, Mathias
c3ade56c-6aa9-4acf-a06b-1c6227175247
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Zender, Lars
2918edd0-368a-4152-8d3c-1689e9b591c6
Gil, Jesús
c5cf7797-79f2-4e17-b714-eefb79214181

Georgilis, Athena, Klotz, Sabrina, Hanley, Christopher J., Herranz, Nicolas, Weirich, Benedikt, Morancho, Beatriz, Leote, Ana Carolina, D'Artista, Luana, Gallage, Suchira, Seehawer, Marco, Carroll, Thomas, Dharmalingam, Gopuraja, Wee, Keng Boon, Mellone, Marco, Pombo, Joaquim, Heide, Danijela, Guccione, Ernesto, Arribas, Joaquín, Barbosa-Morais, Nuno L., Heikenwalder, Mathias, Thomas, Gareth J., Zender, Lars and Gil, Jesús (2018) PTBP1-Mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell, 34 (1), 85-102.e9. (doi:10.1016/j.ccell.2018.06.007).

Record type: Article

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. 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.

Text
1-s2.0-S1535610818302642-main - Version of Record
Available under License Creative Commons Attribution.
Download (6MB)

More information

Accepted/In Press date: 11 June 2018
Published date: 9 July 2018
Keywords: alternative splicing, EXOC7, Oncogene-induced senescence, PTBP1, RNAi screen, SASP, senescence

Identifiers

Local EPrints ID: 422074
URI: https://eprints.soton.ac.uk/id/eprint/422074
ISSN: 1535-6108
PURE UUID: ea5dcd0a-7bad-4903-b90f-7f4ea45b4214
ORCID for Christopher J. Hanley: ORCID iD orcid.org/0000-0003-3816-7220
ORCID for Marco Mellone: ORCID iD orcid.org/0000-0002-4964-9340

Catalogue record

Date deposited: 16 Jul 2018 16:30
Last modified: 14 Mar 2019 01:38

Export record

Altmetrics

Contributors

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×