Dissecting the Relationship between Mucin 5AC and the Lung/Gut Microbiome in the Pathogenesis of K-ras Mutant Lung Cancer

Advisor: Seyed Javad Moghaddam, MD

Non-small cell lung cancer, including its most common subtype, lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. In LUAD patients, KRAS mutations are the most common oncogenic driver alteration. Given KRAS is upstream to many signaling pathways involved in cell survival and cytokine production, interventions against KRAS-mutant lung cancers are prone to develop acquired resistance. Thus, there is a need to develop alternate targeting strategies and test combination therapies for improved intervention. Previously, we have found that KRAS-mutant LUAD (KM-LUAD) patients whose tumors harbor high expression of Mucin 5 AC (MUC5AC), a main airway secretory mucin, have a poor prognosis and significantly lower survival rate. Additionally, evaluation of MUC5AC-deletion in our murine model of KM-LUAD demonstrated a significant reduction in tumor burden. Given the known effect of mucin polymers on bacterial growth and the immune microenvironment in the context of other airway inflammatory diseases, this work aims to better understand the MUC5AC-to-microbiome relationship and test the combinatorial effects of MUC5AC-deficiency and pan-microbiome depletion on tumor progression, the lung immune contexture, and microbiome (lung and gut) using a lung epithelial specific mouse model of KM-LUAD. We found that the combination of MUC5AC-deficiency with pan-microbiome depletion significantly reduced the tumor burden and diminished the pro-tumor immune microenvironment. Additionally, we also found that MUC5AC-deficiency induced lung microbial dysbiosis. These findings suggest that the MUC5AC-to-microbiome relationship is a key target for modulation and could potentially lead to the development of an alternative preventive/therapeutic modality against KM-LUAD.

Advisory Committee:
Seyed Javad Moghaddam, MD, Chair
Dickey Burton, MD
Scott Evans, MD
Edwin Ostrin, MD, PhD
Florencia McAllister, MD

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Meeting ID: 875 8523 0659
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