Lung Cancer (LC) is the leading cause of cancer-related mortality in the world, accounting for ~24% of cancer- related deaths in both women and men. The predicted 5-year survival rate of non-small-cell lung cancer (NSCLC) is 21%. The high mortality rate of LC patients is attributed to the fact that they usually present at an advanced stage where treatment options are mostly palliative. Brain metastasis remains a major cause of morbidity and mortality in lung cancer. Approximately, 25-40% of NSCLC develop central nervous system (CNS) metastasis. Our recent studies have found that MUC5AC is overexpressed in NSCLC and is associated with poor prognosis. Further, Muc5ac is found to be overexpressed in lung tissues of a genetically engineered mouse model (GEMM) (KrasG12D; AdCre and KrasG12D; Trp53R172H/+; AdCre). We have shown that MUC5AC interacts with integrin β4 and leads to lung cancer cell metastasis by activating focal adhesion kinase (FAK). In addition, we observed that MUC5AC expression is increased in brain metastatic tissues of LC. Based on these studies, we hypothesize that MUC5AC is overexpressed in lung cancer and plays a central role in brain metastasis. To test this hypothesis, we propose three specific aims: Aim 1 will define the role of MUC5AC as a biomarker of brain metastasis and establish its clinicopathological significance in lung cancer brain metastases. In Aim 2, we will systemically delineate the molecular mechanisms of MUC5AC on the development of LC brain metastases. It will highlight the mechanistic and functional significance of MUC5AC/integrin β4 axis in cellular adhesion, progression and metastasis of LC and will identify the presence of MUC5AC in exosomes and its role in metastasis. Finally, Aim 3 will identify the biology of MUC5AC mediated brain metastasis and impact of MUC5AC inhibition, using GEMM models. In this aim, we will use our GEM model and decipher the molecular signature and progression and metastasis of lung tumors in the presence and absence of Muc5ac. We will also isolate tumoroid or exosomes from lung cancer patients and GEMM model, including Muc5ac-/- mice to identify metastatic efficiency. We will use MUC5AC targeting antibodies to determine the effects of MUC5AC inhibition on brain metastases, with the goal of developing potential therapeutic options targeted towards brain metastases. Overall, the outcomes from the study will help to identify therapeutic strategies for lung cancer brain metastatic patients.