ST6GalNAc-I/MUC5AC promoting angiogenesis in lung adenocarcinoma

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Abstract Non-small cell lung cancer (NSCLC) is an aggressive disease accounting for approximately 85% of all lung cancers. Despite recent advances, the overall 5-year survival rate remains dismal for NSCLC patients. Lung adenocarcinoma (LUAD) is the most common subtype of NSCLC. A high incidence of LUAD displays an aggressive disease, frequent metastasis and is associated with poor prognosis. Hence, understanding the mechanisms behind LUAD angiogenesis, tumor development, and metastasis would significantly improve LUAD outcomes. The unique expression of St6galnac-I was identified in aggressive type (KrasG12D/+; Trp53R172H/+; Ad- Cre (KPA)) autochthonous tumors. ST6GalNAc-I is an O-glycosyltransferase, which catalyzes the addition of sialic acid onto first sugar GalNAc (Tn) and results in the formation of Neu5Acα2, 6GalNAc (STn) carbohydrate antigen. ST6GalNAc-I KO cells showed a reduced level of sialylated MUC5AC in LUAD cells, and ST6GalNAc- I KO or MUC5AC knockdown (KD) cells had less angiogenesis and migratory potential. In particular, MUC5AC KD LC showed significantly reduced organ-specific endothelial binding and tube formation ability in both lung (HUVEC) and brain (HBEC-5i). Based on these studies, we hypothesize that “ST6GalNAc-I alters MUC5AC glycosylation in the LUAD tumor microenvironment and promotes angiogenesis in both the primary tumor and metastatic sites through integrin β4.” To test this hypothesis, two specific aims are proposed. Aim 1 will comprehensively define the impact of ST6GalNAc-I on MUC5AC glycosylation and its impact on tumor growth and angiogenesis. Aim 2 will systemically delineate the molecular mechanism of ST6GalNAc-I mediated MUC5AC glycosylation and their role in the tumor microenvironment in both primary and metastatic sites, especially brain metastasis, using available mouse models. To prove this concept, we will use ST6GalNAc-I KO or MUC5AC KO cell lines, transthoracic and intracardiac metastatic models, and Muc5ac knockout mouse models. We will also use 3D organoid models to study the interaction of MUC5AC expressing tumor cells and non-tumor cells in primary and metastatic sites. It will highlight the mechanistic and functional significance of the ST6GalNAc-I/MUC5AC axis in cellular adhesion and metastasis. The major impact of the proposed study would be to provide the impact of ST6GalNAc-I on MUC5AC sialylation and the role of this pathway in tumor growth and angiogenesis. The outcomes from the study will help to design novel therapeutic strategies for metastatic LUAD patients.