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 commonly metastasizes to the brain, worsening patient prognosis. Early detection of brain metastases (BMs) is therefore critical, highlighting the need for reliable biomarkers. Gangliosides (GGs)—bioactive glycosphingolipids involved in cellular signaling and immune responses—have emerged as promising candidates. In this context, ion mobility separation mass spectrometry (IMS MS) was used here to analyze GG alterations in LUAD-associated brain metastases (BMLA) compared to healthy cerebellar tissue. The results revealed a reduced diversity of GG species, altered sialylation, and differences in fatty acid and sphingoid base structures. GM3 was overexpressed in BMLA, supporting its role in tumor progression via immune evasion and oncogenic signaling. Brain-specific GT1 and unusual asialogangliosides—absent in normal brain—were also elevated, suggesting their relevance in metastasis and brain adaptation. Structural modifications such as O -acetylation and fucosylation, were more frequent in BMLA, being linked to aggressive tumor traits. Ceramide profiles revealed increased levels of proliferative C16- and C24-ceramides and decreased pro-apoptotic C18-ceramide. Additionally, GD3(d18:1/16:0), identified as a potential BMLA biomarker, was structurally characterized using (–) nanoESI IMS CID MS/MS. These findings underscore the diagnostic and therapeutic promise of GG profiling in LUAD brain metastases.