Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism

Virginie Deswaerte, Paul Nguyen, Alison West, Alison F. Browning, Liang Yu, Saleela M. Ruwanpura, Jesse Balic, Thaleia Livis, Charlotte Girard, Adele Preaudet, Hiroko Oshima, Ka Yee Fung, Hazel Tye, Meri Najdovska, Matthias Ernst, Masanobu Oshima, Cem Gabay, Tracy Putoczki, Brendan J. Jenkins

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Abstract

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1b, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.

Original languageEnglish
Pages (from-to)1293-1307
Number of pages15
JournalCancer Research
Volume78
Issue number5
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Deswaerte, Virginie ; Nguyen, Paul ; West, Alison ; Browning, Alison F. ; Yu, Liang ; Ruwanpura, Saleela M. ; Balic, Jesse ; Livis, Thaleia ; Girard, Charlotte ; Preaudet, Adele ; Oshima, Hiroko ; Fung, Ka Yee ; Tye, Hazel ; Najdovska, Meri ; Ernst, Matthias ; Oshima, Masanobu ; Gabay, Cem ; Putoczki, Tracy ; Jenkins, Brendan J. / Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism. In: Cancer Research. 2018 ; Vol. 78, No. 5. pp. 1293-1307.
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title = "Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism",
abstract = "Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1b, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.",
author = "Virginie Deswaerte and Paul Nguyen and Alison West and Browning, {Alison F.} and Liang Yu and Ruwanpura, {Saleela M.} and Jesse Balic and Thaleia Livis and Charlotte Girard and Adele Preaudet and Hiroko Oshima and Fung, {Ka Yee} and Hazel Tye and Meri Najdovska and Matthias Ernst and Masanobu Oshima and Cem Gabay and Tracy Putoczki and Jenkins, {Brendan J.}",
year = "2018",
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doi = "10.1158/0008-5472.CAN-17-1887",
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Deswaerte, V, Nguyen, P, West, A, Browning, AF, Yu, L, Ruwanpura, SM, Balic, J, Livis, T, Girard, C, Preaudet, A, Oshima, H, Fung, KY, Tye, H, Najdovska, M, Ernst, M, Oshima, M, Gabay, C, Putoczki, T & Jenkins, BJ 2018, 'Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism', Cancer Research, vol. 78, no. 5, pp. 1293-1307. https://doi.org/10.1158/0008-5472.CAN-17-1887

Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism. / Deswaerte, Virginie; Nguyen, Paul; West, Alison; Browning, Alison F.; Yu, Liang; Ruwanpura, Saleela M.; Balic, Jesse; Livis, Thaleia; Girard, Charlotte; Preaudet, Adele; Oshima, Hiroko; Fung, Ka Yee; Tye, Hazel; Najdovska, Meri; Ernst, Matthias; Oshima, Masanobu; Gabay, Cem; Putoczki, Tracy; Jenkins, Brendan J.

In: Cancer Research, Vol. 78, No. 5, 01.03.2018, p. 1293-1307.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism

AU - Deswaerte, Virginie

AU - Nguyen, Paul

AU - West, Alison

AU - Browning, Alison F.

AU - Yu, Liang

AU - Ruwanpura, Saleela M.

AU - Balic, Jesse

AU - Livis, Thaleia

AU - Girard, Charlotte

AU - Preaudet, Adele

AU - Oshima, Hiroko

AU - Fung, Ka Yee

AU - Tye, Hazel

AU - Najdovska, Meri

AU - Ernst, Matthias

AU - Oshima, Masanobu

AU - Gabay, Cem

AU - Putoczki, Tracy

AU - Jenkins, Brendan J.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1b, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.

AB - Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1b, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.

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U2 - 10.1158/0008-5472.CAN-17-1887

DO - 10.1158/0008-5472.CAN-17-1887

M3 - Article

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SP - 1293

EP - 1307

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

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