Year: 2021
Type: conference-abstract
Abstract: Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, is mainly caused by oncogenic mutations like KRAS, which offers limited and unsuccessful treatments. An important aspect of airway homeostasis is the mucus barrier composed of mucins, particularly Mucin5ac (Muc5ac) which is mainly expressed by lung epithelial cells. However, its overproduction can promote respiratory diseases such as chronic obstructive pulmonary disease (COPD), which is known to increase the risk of lung cancer by up to 10fold. Our lab has previously shown that Muc5ac is commonly expressed in patients with KRAS-driven LUAD. We also demonstrated the causal role of this protein in LUAD either induced chemically by urethane or with mice genetically engineered with mutant KRAS G12D (CC-LR) and lack of Muc5ac (CC-LR/Muc5ac -/-). Here, we sought to further dissect the mechanism of tumor promotion by Muc5ac in KRAS mutant lung tumorigenesis. Analysis of bronchoalveolar lavage fluid (BALF) in CC-LR/Muc5ac -/-mice compared to age and sex-matched control CC-LR mice, showed a predominance of macrophages with a significant downregulation of a mucin receptor called "Siglec-E" which is known to be involved in the recruitment of tumor-associated macrophages. The protumorigenic M2 type macrophage polarization marker, Fizz1, was also downregulated in CC-LR/Muc5ac -/- mice. On the other hand, we found significant upregulation of cytotoxic factors, TNF- and Gzmb, suggesting a mechanism mediated by direct tumor cytotoxic activity associated with a reduction in the macrophage-mediated immunosuppressive tumor microenvironment (TME). We also took a translational approach using an antisense oligonucleotide (ASO) against Muc5ac. This was tested by intrapharyngeal administration of either Muc5ac ASO (5mg/kg) or vehicle (saline) twice a week to a cohort of 6-week-old CC-LR mice for a total duration of 8 weeks. This resulted in a 5-fold decrease in Muc5ac mRNA expression and a significant (42%) reduction in overall tumor burden. Additionally, analysis of BALF led to similar findings to that of our CC-LR/Muc5ac -/-mouse model. In conclusion, our study suggests that Muc5ac inhibition can ameliorate the tumorigenic phenotype of mutant KRAS in the lung through potential tumor cell-extrinsic (paracrine) mechanisms by reprogramming the TME. This could pave the way for new prevention and treatment modalities for this largely resilient disease.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4239585221