Open Access

ARTICLE

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

Wen-Hsin Hsu^1,2,#, Kai-Fu Chang^3,4,#, Chih-Hsuan Chang^3,4, Hui-Ru Lin^5,6, Chi-Jen Wu^5,7, Ching-Chung Ko^8,9,10, Cheng-Chun Wu¹¹, Yu-Cheng Ho¹¹, Chih-Chun Lin¹², Chien-Han Yuan^3,5,13,14, Sachin Kumar^15,16, Dahlak Daniel Solomon¹⁵, Fitria Sari Wulandari¹⁵, Juan Lorell Ngadio¹⁷, Do Thi Minh Xuan¹⁸, Chung-Bao Hsieh¹⁹, Chung-Chieh Chiao²⁰, Ngoc Uyen Nhi Nguyen^21,22, Chih-Yang Wang^15,20, Yung-Kuo Lee^3,4,5,*
1 Department of Emergency Medicine, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
2 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan
3 Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
4 Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan
5 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
6 Nursing Department, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
7 College of Nursing, Kaohsiung Medical University, Kaohsiung, Taiwan
8 Department of Medical Imaging, Chi-Mei Medical Center, Tainan, Taiwan
9 Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
10 School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
11 School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
12 Department of Physical Therapy, I-Shou University, Kaohsiung, Taiwan
13 Department of Otolaryngology, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung, Taiwan
14 Department of Otolaryngology, National Defense Medical Center, Taipei, Taiwan
15 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
16 Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Himachal Pradesh, India
17 Department of Bioinformatics, School of Life Sciences, Indonesia International Institute for Life Sciences, Jl. Pulomas Barat Kav 88, Jakarta Timur, Indonesia
18 Faculty of Pharmacy, Van Lang University, 69/68 Dang Thuy Tram Street, Binh Loi Trung Ward, Ho Chi Minh City, Vietnam
19 Division of General Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
20 PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
21 Center for Regenerative Medicine, University of South Florida Health Heart Institute, Tampa, FL, USA
22 Division of Cardiology, Department of Internal Medicine, Morsani School of Medicine, University of South Florida, Tampa, FL, USA
* Corresponding Author: Yung-Kuo Lee. Email:
# These authors contributed equally to this work
(This article belongs to the Special Issue: Tumor Biomarkers for Diagnosis, Prognosis and Targeted Therapy)

Oncology Research https://doi.org/10.32604/or.2026.070445

Received 16 July 2025; Accepted 04 February 2026; Published online 17 March 2026

Abstract

Background: Glycosylation and inflammation are pivotal in tumor progression, yet the specific glycosyltransferases bridging these processes remain poorly defined. This study investigated Exostosin-1 (EXT1), a key enzyme in heparan sulfate (HS) biosynthesis, as a mechanistic bridge connecting inflammation, stromal remodeling, and immune evasion-driven cancers. Methods: We used a multi-omics approach including Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression on The Cancer Genome Atlas (TCGA) pan-cancer cohorts, transcriptomics, survival, single-cell RNA sequencing (scRNA-seq), DNA methylation profiling, pathway enrichment analysis (MetaCore), molecular docking, and immunohistochemistry (IHC) on pancreatic adenocarcinoma (PAAD) and lung adenocarcinoma (LUAD) tissue microarrays. Results: EXT1 was identified as one of only two genes overlapping inflammation- and glycosylation-related gene sets, strongly associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) across cancers, particularly in PAAD and LUAD. Pan-cancer profiling revealed broad EXT1 upregulation. ScRNA-seq localizedEXT1to stromal cells (pancreatic stellate cells, fibroblasts) and epithelial cells co-expressed with immune checkpoint markers. EXT1 promoter hypomethylation correlated with high expression and poor survival. Enrichment analysis of EXT1-correlated genes highlighted activation of critical pro-tumorigenic pathways, including transforming growth factor-β (TGF-β), lysophosphatidic acid (LPA), epidermal growth factor receptor-phosphoinositide 3-kinase-AKT–mitogen-activated protein kinase (EGFR-PI3K-AKT-MAPK), integrin-focal adhesion kinase-Rho GTPase (integrin–FAK–Rho), and epithelial–mesenchymal transition (EMT) pathways. IHC validated stage-dependent EXT1 overexpression in both PAAD and LUAD. Conclusion: This multi-omics study identifies EXT1 as a novel link between glycosylation and inflammation. It functions as a driver of stromal activation, immune checkpoint engagement, and tumor progression. EXT1 represents a clinically relevant biomarker and a promising therapeutic target in inflammation-driven cancers like PAAD and LUAD.

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Keywords

Exostosin-1; inflammation; glycosylation; machine learning; cancer prognosis; immune evasion; immunotherapy biomarker

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