title: Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.
abstract: Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130F/Fknock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130F/F:KrasG12Dmodel, but not parental KrasG12Dmice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130F/F:KrasG12Dmice revealed the upregulation of IL-6 and STAT3-target genes compared with KrasG12Dmuscle tissue. These cachectic features of gp130F/F:KrasG12Dmice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130F/F:KrasG12D:Stat3-/+or gp130F/F:KrasG12D:Il6-/-mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130F/F:KrasG12Dmice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130F/F:KrasG12Dmice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|General and Respiratory Medicine, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.|Department of Biological Sciences, Rabigh College of Science and Art, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: S
authors.initials: S
authors.lastname: Alhayyani
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Szczepny
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.
authors.forename: D N
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Enriori
authors.affiliation: NovImmune SA, Geneva, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Ferlin
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Ruwanpura
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C577686:interleukin-6, mouse; D015850:Interleukin-6