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  3. Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis

Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis

  • Int J Med Sci. 2025 Sep 27;22(15):4102-4118. doi: 10.7150/ijms.116954.
Fitria Sari Wulandari 1 2,  Chih-Yang Wang 1 3 4,  Sachin Kumar 1 5,  Ngoc Phung Ly 1,  Juan Lorell Ngadio 1 6,  Dahlak Daniel Solomon 1 7,  Do Thi Minh Xuan 8,  Gabriela Natasha Sutandi 1 9,  Hung-Yun Lin 1 4 10 11 12,  Hui-Ru Lin 13 14,  Yung-Kuo Lee 13 15 16,  Hao-Chien Yang 2,  Ming-Cheng Tsai 17 18,  Ching-Chung Ko 19 20 21
Affiliations

Affiliations

  • 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 Department of Surgery, Division of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
  • 3 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 4 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 5 Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Himachal Pradesh, 173229, India.
  • 6 Department of Bioinformatics, School of Life Sciences, Indonesia International Institute for Life Sciences, Jl. Pulomas Barat Kav 88, Jakarta Timur, 13210, Indonesia.
  • 7 Yogananda School of AI Computers and Data Sciences, Shoolini University, Solan 173229, India.
  • 8 Faculty of Pharmacy, Van Lang University, 69/68 Dang Thuy Tram Street, Binh Loi Trung Ward, Ho Chi Minh City 70000, Vietnam.
  • 9 Division of Biology and Bioinformatics, School of Bioscience, University of Skövde, Högskolevägen 1, PO Box 408, 541 28 Skövde, Sweden.
  • 10 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
  • 11 Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
  • 12 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
  • 13 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
  • 14 Nursing Department, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
  • 15 Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 11490, Taiwan.
  • 16 Medical laboratory, Medical Education and Research Center, Kaohsiung 80284, Taiwan.
  • 17 School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan.
  • 18 Department of Neurosurgery, Shin-Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang Road, Shih-Lin District, Taipei 111045, Taiwan.
  • 19 Department of Medical Imaging, Chi Mei Medical Center, Tainan, 71004, Taiwan.
  • 20 Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, 71710, Taiwan.
  • 21 School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan.
PMID: 41049440 DOI: 10.7150/ijms.116954
Abstract

Glioblastoma multiforme (GBM) is characterized by rapid progression, therapeutic resistance, and a profoundly immunosuppressive tumor microenvironment. Emerging evidence suggests that endoplasmic reticulum (ER)-associated macromolecules play critical roles in tumor adaptation. In this study, we performed a multi-omics investigation of orosomucoid-like protein 2 (ORMDL2), a conserved ER membrane protein involved in sphingolipid biosynthesis and ER stress regulation, and uncovered its regulatory functions in GBM progression. Transcriptomic analyses across The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) revealed elevated ORMDL2 expression in GBM tissues which causes poor prognosis. The MetaCore pathway and Gene Set Enrichment Analysis (GSEA) identified ORMDL2's involvement in antigen presentation via a major histocompatibility complex I (MHC class I), unfolded protein response (UPR), and mitochondrial apoptotic signaling. Single-cell RNA-sequencing data and the Human Protein Atlas showed ORMDL2 enrichment in tumor stromal cells. Pharmacogenomic correlation via the Genomics in Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) database suggested that ORMDL2 expression was associated with resistance to DNA damage response inhibitors such as etoposide, doxorubicin, talazoparib, and might interact with sphingolipid-targeting compounds. Collectively, our findings establish ORMDL2 as a multi-functional macromolecular regulator of immune suppression and therapeutic resistance in GBM, providing new mechanistic insights and potential targets for translational medicines.

Keywords

Drug Discovery; Glioblastoma; Multi-omics Analysis; ORMDL2; Tumor Microenvironment (TME).

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