20170203-Brooks-Thesis.pdf (3.87 MB)
Deregulated IL-6/gp130 signalling in lung cancer development
thesis
posted on 2017-02-13, 04:19 authored by Gavin BrooksLung cancer is the
most common and lethal form of cancer in Australia and worldwide, with lung
adenocarcinoma (LAC) being the most common phenotype of lung cancer. LAC is
strongly associated with chronic lung inflammation triggered by cigarette
smoking, and one of the most established disease-associated consequences of the
genotoxic effects of cigarette-derived carcinogens is activating mutations in
the Kras proto-oncogene. The identification of activating mutations in a
minority of LAC patients, mainly comprising never smokers, has paved the way
for targeted therapies with substantial benefit. However, effective therapies
for LAC with a more typical mutation profiles, especially those associated with
smoking, are yet to be identified, thus highlighting the need for a better
understanding of the molecular and genetic alterations involved in the
initiation and progression of LAC. In this regard, components of the IL-6
cytokine family which signal through the shared gp130 signal-transducing
receptor subunit, are commonly up-regulated in human lung cancer, and
represents a promising target in anti-cancer therapy. Despite this, the
molecular mechanisms associated with deregulated gp130 signalling in lung
cancer has not been fully elucidated, largely due to the paucity of genetically
defined pre-clinical mouse models that allow for identification of gp130
signalling pathway-related diseases.
This thesis addresses the question whether gp130 signalling contributes to the initiation and maintenance of the malignant phenotype of LAC by enhancing the oncogenic effects of mutated Kras. We utilised our novel gp130F/F mouse model for upregulated endogenous IL-6 production and associated spontaneous pulmonary inflammation as a result of a “knock-in” substitution within the IL-6 family co-receptor gp130. These mice display augmented activation of the latent transcription factor Stat3 in the absence of gp130-driven PI3K/Akt and Mapk/Erk signalling. Importantly, Stat3, PI3K/Akt and Mapk/Erk have been implicated in lung cancer development.
We used gp130F/F mice generated onto the lung cancer susceptible genetic background Kras(G12D) (gp130F/F:KrasG12D mice) and elucidated for the first time that gp130 signalling driven cell proliferation augmented Kras-induced lung carcinogenesis. Importantly, we discovered a causal role for IL-6 via its pathogenic mode IL-6 trans signalling, as well as identify a potential therapeutic strategy to target discrete modes of IL-6 signalling in Kras-induced LAC. We also identified Stat3 as the downstream mediator of IL-6/gp130 driven inflammation associated with Kras-induced LAC. Furthermore, we validated above findings in clinical setting using lung cancer biopsies.
These results will therefore provide a significant and original contribution to our fundamental understanding of the mechanisms involved in lung cancer that will potentially strengthen the translational impact of early detection and treatment of the disease in the clinic.
This thesis addresses the question whether gp130 signalling contributes to the initiation and maintenance of the malignant phenotype of LAC by enhancing the oncogenic effects of mutated Kras. We utilised our novel gp130F/F mouse model for upregulated endogenous IL-6 production and associated spontaneous pulmonary inflammation as a result of a “knock-in” substitution within the IL-6 family co-receptor gp130. These mice display augmented activation of the latent transcription factor Stat3 in the absence of gp130-driven PI3K/Akt and Mapk/Erk signalling. Importantly, Stat3, PI3K/Akt and Mapk/Erk have been implicated in lung cancer development.
We used gp130F/F mice generated onto the lung cancer susceptible genetic background Kras(G12D) (gp130F/F:KrasG12D mice) and elucidated for the first time that gp130 signalling driven cell proliferation augmented Kras-induced lung carcinogenesis. Importantly, we discovered a causal role for IL-6 via its pathogenic mode IL-6 trans signalling, as well as identify a potential therapeutic strategy to target discrete modes of IL-6 signalling in Kras-induced LAC. We also identified Stat3 as the downstream mediator of IL-6/gp130 driven inflammation associated with Kras-induced LAC. Furthermore, we validated above findings in clinical setting using lung cancer biopsies.
These results will therefore provide a significant and original contribution to our fundamental understanding of the mechanisms involved in lung cancer that will potentially strengthen the translational impact of early detection and treatment of the disease in the clinic.