Overexpression of GM3 and Ganglioside Pattern Remodeling in Lung Adenocarcinoma Brain Metastases Identified by Ion Mobility Mass Spectrometry

Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung carcinoma (NSCLC), commonly metastasizes to the brain, particularly in advanced stages. Since brain metastases (BMs) are a leading cause of morbidity and mortality in LUAD patients, their early detection is critical, necessitating the identification of reliable biomarkers. Gangliosides (GGs), a class of bioactive glycosphingolipids involved in cell signaling, adhesion, and immune regulation, have emerged as promising candidates for diagnostic and therapeutic targeting in LUAD-associated brain metastases (BMLA). In this context, ion mobility spectrometry mass spectrometry (IMS-MS) was employed here to analyze GG alterations in BMLA tissues compared to healthy cerebellar control. The results revealed marked differences, including a reduction in the total number of species, altered sialylation profiles, and variations in fatty acid chain length and sphingoid base hydroxylation. GM3, a monosialodihexosylganglioside, was significantly overexpressed in BMLA, supporting its role in tumor progression via immune evasion and oncogenic signaling. Elevated levels of the brain-specific GT1 ganglioside further point to its possible role as a metastasis-associated biomarker, while the presence of asialogangliosides, absent in normal brain, suggests adaptation to the brain microenvironment. Structural modifications such as <i>O</i>-acetylation, fucosylation, and CH₃COO^- were more frequent in BMLA, being associated with aggressive tumor phenotypes. Ceramide profiles revealed increased levels of proliferative C16- and C24-ceramides and decreased pro-apoptotic C18-ceramide. Additionally, GM3(d18:1/22:0) and GD3(d18:1/16:0), identified as potential BMLA biomarkers, were structurally characterized using (-) nanoelectrospray ionization (nanoESI) IMS collision-induced dissociation tandem MS (CID MS/MS). Collectively, these findings highlight the clinical potential of GGs for early diagnosis and targeted therapy in BMLA.