Abstract 1283: MUC5AC promotes brain metastases and colonization in non small cell lung cancer

Abstract Background: Non-small cell lung adenocarcinoma (NSCLC), constitutes 80-85% of the lung cancers. The 5-year survival of patients with metastatic lung cancer is only 5%. Additionally, the prognosis worsens in NSCLC patients (40-50%) that have developed brain metastasis. Mucin 5AC (MUC5AC) is overexpressed in the primary NSCLC and brain metastatic tissues; however, the mechanism in the MUC5AC-mediated brain metastasis is unclear. Methods: Immunohistochemistry was performed on lung cancer samples. Expression studies were conducted in the brain-tropic cell lines (A549-BrM, PC9-BrM, and HCC4006-BrM cells) and their respective parental lines. CRISPR Cas9 or shRNA was used to either knockout/knockdown MUC5AC in the cell lines. Mass-spectrometry analysis and protein arrays were conducted in the brain trophic cells. In vivo mouse models involving intracardiac injection of cancer cells were performed, and the effect of MUC5AC brain metastasis and survival was analyzed. Results: MUC5AC was significantly increased in NSCLC brain metastatic tissues. Similarly, MUC5AC expression was elevated in NSCLC brain tropic (BrM) cell lines compared to parental lines. Treatment of BrM or parental cells with the conditioned media of normal human astrocytes resulted in increased MUC5AC levels. We observed astrocyte-derived CCL2-induced the MUC5AC expression in both parental and BrM cells. Mass-spectrometry based proteomic analysis indicated decreased cell adhesion molecules such as ALCAM, ITGB4, ITGB5, CDH17, and DSG2 in MUC5AC knockdown tropic cells. Further, Mass-spectrometry based interactome studies revealed MUC5AC interaction with Annexin A2 enabling the cancer cell adhesion. Intracardiac injection of MUC5AC knockdown A549-BrM (A549-BrM-shMUC5AC) cells showed a significant reduction in brain metastasis and increased survival of the mice compared to scramble control group (P<0.001). Conclusion: Our study identified the role of MUC5AC in metastasis and colonization in the brain environment. Mechanistically, MUC5AC interacts with the Annexin A2 during metastasis, while astrocyte derived CCL2 further induced the MUC5AC expression facilitating the colonization of the NSCLC cells in the brain. Hence, targeting MUC5AC and its interactions partner Annexin A2 may prevent NSCLC brain metastasis. Citation Format: Sanjib Chaudhary, Shailendra Kumar Maurya, Jawed Siddiqui, Mohd W. Nasser, Surinder K. Batra, Imayavaramban Lakshmanan, Apar Kishor Ganti. MUC5AC promotes brain metastases and colonization in non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1283.