Multi-Omics and Single-Cell Dissection Reveals EXT1 as a Glycosylation-Linked Therapeutic Target in Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Glycosylation and inflammation are critical in cancer, but the enzymes connecting them are unclear.
• Exostosin-1 (EXT1), involved in heparan sulfate (HS) biosynthesis, is investigated as a link between inflammation, stromal remodeling, and immune evasion in cancer.

Purpose of the Study:

• To elucidate the role of Exostosin-1 (EXT1) in connecting inflammation and glycosylation in cancer.
• To evaluate EXT1 as a potential biomarker and therapeutic target in inflammation-driven cancers.

Main Methods:

• Multi-omics approach: LASSO Cox regression, transcriptomics, survival analysis, scRNA-seq, DNA methylation, pathway analysis (MetaCore), molecular docking, and IHC.
• Utilized The Cancer Genome Atlas (TCGA) pan-cancer data and tissue microarrays for pancreatic adenocarcinoma (PAAD) and lung adenocarcinoma (LUAD).

Main Results:

• EXT1 identified as a key gene linking inflammation and glycosylation, associated with poor survival (OS, DSS, PFS) across cancers, especially PAAD and LUAD.
• EXT1 is upregulated pan-cancer, localized in stromal and epithelial cells co-expressing immune checkpoint markers, and its expression correlates with promoter hypomethylation and poor survival.
• EXT1-correlated gene analysis revealed activation of pro-tumorigenic pathways (TGF-β, LPA, EGFR-PI3K-AKT-MAPK, integrin-FAK-Rho, EMT); IHC confirmed stage-dependent overexpression.

Conclusions:

• EXT1 acts as a novel link between glycosylation and inflammation, driving stromal activation, immune checkpoint engagement, and tumor progression.
• EXT1 is a clinically relevant biomarker and a promising therapeutic target for inflammation-driven cancers such as PAAD and LUAD.