Establishing a murine model for early stage squamous cell lung carcinoma and understanding the role of gut microbiota in lung adenocarcinoma

Non-small cell Lung cancer (NSCLC), a subtype of lung cancer (LC), is one of the leading causes of death globally. Over the past decade, the number of LC cases reported has increased substantially. It is estimated that total number of new cases of LC registered in Australia is ~13,000/year. Although there is advancement of endoscopic minimally invasive techniques, surgery is the most standard treatment for LC. Moreover, a 5-year survival rate is observed only in 15% of all the cases because of the advance stage of the disease at the time of diagnosis. New advanced approaches are urgently needed to identify, target and treat LC. Although NSCLC has been extensively studied in the last decade, lack of animal models that could demonstrate the hallmark features of squamous cell carcinoma (SCC), a subtype of NSCLC, is limited. Establishing a murine model that recapitulates the hallmark features of human SCC, to identify prognostic, predictive biomarkers and genetic alterations will reveal underlying molecular targets. This will result in early detection which might help in curative treatment of invasive SCC. Although numerous murine models of adenocarcinoma (AC), another subtype of LC, have been established recently, the treatment strategies are still limited. Increasing evidence has established the role of gut microbiome in chronic diseases including chronic obstructive pulmonary disease (COPD) and also in colon and breast cancers. However, the role of the gut microbiome in AC progression is still unclear. Identifying the role of the gut microbiome in LC progression would establish a new platform for novel therapies to treat AC patients. Although SCC is more strongly associated with CS there is no established mouse model of the same. Previous studies have used N-nitroso-tris-chloroethylurea (NTCU) to induce SCC in mice model, however the mutations identified were nonsynonymous to human patients and had ethical challenges such as high mortality rate. Thus, in Chapters 4 and 5 of thesis, I have used NTCU along with CS to establish a novel mouse model for SCC using A/J mice and C57BL/6 mice. In these chapters, usage of low dose NTCU and CS exposure has led to the development of early stages of SCC in the two different strains of mice (A/j and C57BL/6). In Chapter 6 of this thesis, we explore the role of altering the gut microbiome in AC. As the gut microbiome is seen to have a major influence on lung health, the changes induced by carcinogens and CS may influence the development and progression of LC through a variety of pathways (short-chain fatty acids [SCFA], bile salts). There has been no studies characterizing the influence of the microbiome on LC development and progression. As CS is known to alter gut microbiota, CS-induced altered gut microbiome and associated metabolites could also influence CS+NNK induced AC. Thus, we manipulated the microbiome by transfer of faeces from healthy controls to carcinogen exposed mice as a therapeutic strategy to slow the development and progression of CS+NNK induced AC. These studies can further be characterized to identify the early diagnostic markers for SCC patients and perform therapeutic studies of AC.