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 gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) 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 trans-signaling, 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.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Brooks
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Sultan
authors.initials: S
authors.lastname: Alhayyani
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Alistair
authors.initials: A
authors.lastname: Miller
authors.affiliation: St Vincent's Hospital, Fitzroy, Victoria, Australia. Department of Pathology, Melbourne Medical School, Melbourne University, Parkville, Victoria, Australia.
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Russell
authors.affiliation: NovImmune SA, Geneva, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Saleela
authors.initials: S
authors.lastname: Ruwanpura
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia. brendan.jenkins@hudson.org.au.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D016283:Proto-Oncogene Proteins p21(ras)