Dissecting the role of gut microbiome dysbiosis in lung cancer development and progression.

PROJECT SUMMARY Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer (NSCLC) and is, for the most part, causally related to tobacco exposure. Despite recent advances in treatment (e.g., immunotherapy), LUAD patients still often display poor prognosis in part due to inferior therapeutic responses and late diagnosis. There is a pressing need for effective strategies to prevent or treat early-stage LUAD in high-risk individuals such as lifetime smokers. Accumulating evidence has shown that microorganisms in the gut can shape overall immunity and influence states of health and disease, including cancer at the systemic level. Yet, we still do not fully understand the role of the gut and host microbiome in development of LUAD, the most common type of malignancy outside the gastrointestinal tract. We previously showed that gut microbiome changes are strongly associated with development of LUAD in a human-relevant, tobacco-associated mouse model (Gprc5a-/-; G). On top of this, knockout of Lcn2, an antimicrobial protein, in these mice (Gprc5a-/-/Lcn2-/-; GL) reduced microbial diversity while enhancing inflammation, including expression of various pro-inflammatory cytokines such as IL- 6, and lung tumor development. These earlier and preliminary findings motivate my hypothesis that gut microbial dysbiosis (such as that incurred by Lcn2 loss) can stimulate a systemic inflammatory cascade conducive to tumor growth via an IL-6-dependent pathway. I will address this hypothesis through two aims. Aim 1 will determine how gut dysbiosis impacts immunomodulation and inflammation during LUAD development. Using genetic deletion (global and immune-subset specific) and pharmacological inhibition strategies, I will dissect the role of the IL- 6/STAT3 pathway downstream of gut microbiome dysbiosis in LUAD pathogenesis and immune responses. Aim 2 will interrogate the preventive and early therapeutic roles of specific bacterial taxa, alone or in combination with anti-inflammatory agents, in mitigating LUAD pathogenesis. Specifically, I will examine the effects of Limosilactobacillus reuteri treatment in tobacco carcinogen-exposed animals on LUAD pathogenesis, including in combination with strategies targeting IL-6/STAT3 signaling. Leveraging human-relevant mouse models and cutting-edge immune profiling techniques, I aim to unravel the intricate interplay between gut dysbiosis, inflammation, and LUAD development, paving the way for innovative prevention and early intervention strategies. This research endeavor not only seeks to deepen our understanding of host mechanisms governing LUAD progression but also pave way for development of novel avenues for prevention and treatment, potentially incorporating probiotic interventions. By targeting high-risk individuals, such as smokers, with tailored approaches, we aspire to alleviate the burden of LUAD and improve outcomes for affected individuals.