IL6 trans-signaling promotes KRAS-driven lung carcinogenesis

Gavin D. Brooks, Louise McLeod, Sultan Alhayyani, Alistair Miller, Prudence A Russell, Walter Ferlin, Stefan Rose-John, Saleela Ruwanpura, Brendan J. Jenkins

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

Abstract

Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.

Original languageEnglish
Pages (from-to)866-876
Number of pages11
JournalCancer Research
Volume76
Issue number4
DOIs
Publication statusPublished - 15 Feb 2016

Cite this

Brooks, Gavin D. ; McLeod, Louise ; Alhayyani, Sultan ; Miller, Alistair ; Russell, Prudence A ; Ferlin, Walter ; Rose-John, Stefan ; Ruwanpura, Saleela ; Jenkins, Brendan J. / IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. In: Cancer Research. 2016 ; Vol. 76, No. 4. pp. 866-876.
@article{44743f225da84751ab3b161a00a9192f,
title = "IL6 trans-signaling promotes KRAS-driven lung carcinogenesis",
abstract = "Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.",
author = "Brooks, {Gavin D.} and Louise McLeod and Sultan Alhayyani and Alistair Miller and Russell, {Prudence A} and Walter Ferlin and Stefan Rose-John and Saleela Ruwanpura and Jenkins, {Brendan J.}",
year = "2016",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-15-2388",
language = "English",
volume = "76",
pages = "866--876",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research",
number = "4",

}

Brooks, GD, McLeod, L, Alhayyani, S, Miller, A, Russell, PA, Ferlin, W, Rose-John, S, Ruwanpura, S & Jenkins, BJ 2016, 'IL6 trans-signaling promotes KRAS-driven lung carcinogenesis', Cancer Research, vol. 76, no. 4, pp. 866-876. https://doi.org/10.1158/0008-5472.CAN-15-2388

IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. / Brooks, Gavin D.; McLeod, Louise; Alhayyani, Sultan; Miller, Alistair; Russell, Prudence A; Ferlin, Walter; Rose-John, Stefan; Ruwanpura, Saleela; Jenkins, Brendan J.

In: Cancer Research, Vol. 76, No. 4, 15.02.2016, p. 866-876.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - IL6 trans-signaling promotes KRAS-driven lung carcinogenesis

AU - Brooks, Gavin D.

AU - McLeod, Louise

AU - Alhayyani, Sultan

AU - Miller, Alistair

AU - Russell, Prudence A

AU - Ferlin, Walter

AU - Rose-John, Stefan

AU - Ruwanpura, Saleela

AU - Jenkins, Brendan J.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.

AB - Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.

UR - http://www.scopus.com/inward/record.url?scp=84960338835&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-2388

DO - 10.1158/0008-5472.CAN-15-2388

M3 - Article

VL - 76

SP - 866

EP - 876

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 4

ER -

Brooks GD, McLeod L, Alhayyani S, Miller A, Russell PA, Ferlin W et al. IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. Cancer Research. 2016 Feb 15;76(4):866-876. https://doi.org/10.1158/0008-5472.CAN-15-2388