A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Juan Carlos Acosta; Ana Banito; Torsten Wuestefeld; Athena Georgilis; Peggy Janich; Jennifer P Morton; Dimitris Athineos; Tae-Won Kang; Felix Lasitschka; Mindaugas Andrulis; Gloria Pascual; Kelly J Morris; Sadaf Khan; Hong Jin; Gopuraja Dharmalingam; Ambrosius P Snijders; Thomas Carroll; David Capper; Catrin Pritchard; Gareth J Inman; Thomas Longerich; Owen J Sansom; Salvador Aznar Benitah; Lars Zender; Jesús Gil

doi:10.1038/ncb2784

A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Juan Carlos Acosta, Ana Banito, Torsten Wuestefeld, Athena Georgilis, Peggy Janich, Jennifer P Morton, Dimitris Athineos, Tae-Won Kang, Felix Lasitschka, Mindaugas Andrulis, Gloria Pascual, Kelly J Morris, Sadaf Khan, Hong Jin, Gopuraja Dharmalingam, Ambrosius P Snijders, Thomas Carroll, David Capper, Catrin Pritchard, Gareth J InmanThomas Longerich, Owen J Sansom, Salvador Aznar Benitah, Lars Zender, Jesús Gil

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

Original language	English
Pages (from-to)	978-90
Number of pages	13
Journal	Nature Cell Biology
Volume	15
Issue number	8
DOIs	https://doi.org/10.1038/ncb2784
Publication status	Published - Aug 2013

Keywords / Materials (for Non-textual outputs)

Animals
Cell Aging
Cell Line, Tumor
Colonic Neoplasms
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Inflammasomes
Interleukin-1
Mice
Models, Animal
Paracrine Communication
Protein Binding
Signal Transduction
Transforming Growth Factor beta1

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10.1038/ncb2784

A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Published in final edited form as: Nat Cell Biol. Aug 2013; 15(8): 978–990.
Accepted author manuscript, 4.47 MB

http://www.nature.com/ncb/journal/v15/n8/full/ncb2784.html

Cite this

Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., Pascual, G., Morris, K. J., Khan, S., Jin, H., Dharmalingam, G., Snijders, A. P., Carroll, T., Capper, D., Pritchard, C., ... Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology, 15(8), 978-90. https://doi.org/10.1038/ncb2784

@article{f3c5a6dc6edc4662aa343f4a39f129a0,

title = "A complex secretory program orchestrated by the inflammasome controls paracrine senescence",

abstract = "Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.",

keywords = "Animals, Cell Aging, Cell Line, Tumor, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Inflammasomes, Interleukin-1, Mice, Models, Animal, Paracrine Communication, Protein Binding, Signal Transduction, Transforming Growth Factor beta1",

author = "Acosta, {Juan Carlos} and Ana Banito and Torsten Wuestefeld and Athena Georgilis and Peggy Janich and Morton, {Jennifer P} and Dimitris Athineos and Tae-Won Kang and Felix Lasitschka and Mindaugas Andrulis and Gloria Pascual and Morris, {Kelly J} and Sadaf Khan and Hong Jin and Gopuraja Dharmalingam and Snijders, {Ambrosius P} and Thomas Carroll and David Capper and Catrin Pritchard and Inman, {Gareth J} and Thomas Longerich and Sansom, {Owen J} and Benitah, {Salvador Aznar} and Lars Zender and Jes{\'u}s Gil",

year = "2013",

month = aug,

doi = "10.1038/ncb2784",

language = "English",

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pages = "978--90",

journal = "Nature Cell Biology",

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Acosta, JC, Banito, A, Wuestefeld, T, Georgilis, A, Janich, P, Morton, JP, Athineos, D, Kang, T-W, Lasitschka, F, Andrulis, M, Pascual, G, Morris, KJ, Khan, S, Jin, H, Dharmalingam, G, Snijders, AP, Carroll, T, Capper, D, Pritchard, C, Inman, GJ, Longerich, T, Sansom, OJ, Benitah, SA, Zender, L & Gil, J 2013, 'A complex secretory program orchestrated by the inflammasome controls paracrine senescence', Nature Cell Biology, vol. 15, no. 8, pp. 978-90. https://doi.org/10.1038/ncb2784

TY - JOUR

T1 - A complex secretory program orchestrated by the inflammasome controls paracrine senescence

AU - Acosta, Juan Carlos

AU - Banito, Ana

AU - Wuestefeld, Torsten

AU - Georgilis, Athena

AU - Janich, Peggy

AU - Morton, Jennifer P

AU - Athineos, Dimitris

AU - Kang, Tae-Won

AU - Lasitschka, Felix

AU - Andrulis, Mindaugas

AU - Pascual, Gloria

AU - Morris, Kelly J

AU - Khan, Sadaf

AU - Jin, Hong

AU - Dharmalingam, Gopuraja

AU - Snijders, Ambrosius P

AU - Carroll, Thomas

AU - Capper, David

AU - Pritchard, Catrin

AU - Inman, Gareth J

AU - Longerich, Thomas

AU - Sansom, Owen J

AU - Benitah, Salvador Aznar

AU - Zender, Lars

AU - Gil, Jesús

PY - 2013/8

Y1 - 2013/8

N2 - Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

AB - Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

KW - Animals

KW - Cell Aging

KW - Cell Line, Tumor

KW - Colonic Neoplasms

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunohistochemistry

KW - Inflammasomes

KW - Interleukin-1

KW - Mice

KW - Models, Animal

KW - Paracrine Communication

KW - Protein Binding

KW - Signal Transduction

KW - Transforming Growth Factor beta1

U2 - 10.1038/ncb2784

DO - 10.1038/ncb2784

M3 - Article

C2 - 23770676

SN - 1465-7392

VL - 15

SP - 978

EP - 990

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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