Glioportal: a comprehensive transcriptomic resource unveiling ligand-mediated mesenchymal transition in glioblastoma
Artikel i vetenskaplig tidskrift, 2025
Background Multi-omics profiling of glioblastoma (GBM) has unraveled two aspects fundamental to its aggressiveness and lethality that is molecular heterogeneity inherent to the tumor and cellular plasticity modulated by the microenvironment. Yet, empirical validation to identify causal factors for these complex mechanisms is rather scarce. Here, we report our endeavor in establishing Glioportal, a GBM tumor biobank with derivative preclinical models and molecular information that we leverage for basic and translational research on precision therapies.Methods Bulk transcriptome and single-cell-based deconvolution analyses highlighted key features of distinct GBM subtypes and ligand-receptor pairs predicted to regulate malignant cell state plasticity. Synthetic genetic tracing tool and target genes/proteins expression analyses validated ligands-induced mesenchymal transition. This was further corroborated with phenotypic invasion/migration assays and cell-based assays using inhibitors, functional antibodies, and gene silencing approaches. A proof-of-concept animal experiment was conducted using orthotopic xenograft carrying gene knockdown. Clinical relevance was assessed through immunohistochemical assay.Results Our transcriptomic analysis highlights the integral roles of STAT3 and NF-kappa B pathways in maintaining intrinsic mesenchymal identity and enabling myeloid-induced plasticity towards mesenchymal phenotype. One critical ligand, TNF, confers mesenchymal adaptation and cellular invasiveness that is mitigated by TNFRSF1A, but not TNFRSF1B, loss of function. TNFRSF1A silencing significantly improves survival in vivo.Conclusion Glioportal makes a valuable resource for identifying therapeutic vulnerabilities in molecularly stratified GBM. Here, we underscore GBM dependency on myeloid-derived ligands to acquire mesenchymal traits that have clinical implications in therapeutic response and recurrence. Such reliance warrants treatment strategies targeting ligand-receptor pairs to mitigate interactions with the tumor ecosystem.
ligand-receptor interaction
cellular plasticity
tumor necrosis factor
glioblastoma tumor resource
mesenchymal transition
Författare
Qing You Pang
National Neuroscience Institute
Wisna Novera
National Neuroscience Institute
Lynnette Wei Hsien Koh
National Neuroscience Institute
Yuk Kien Chong
National Neuroscience Institute
See Wee Lim
National Neuroscience Institute
Ngak Leng Sim
Agency for Science, Technology and Research (A*STAR)
Simone Rizzetto
Agency for Science, Technology and Research (A*STAR)
Jinyue Liu
Agency for Science, Technology and Research (A*STAR)
Xuling Lin
National Neuroscience Institute
Samantha Ya Lyn Ang
National Neuroscience Institute
Duke-NUS Medical School
Justin Rui-Xin Ker
National Neuroscience Institute
Duke-NUS Medical School
Kai-Rui Wan
Duke-NUS Medical School
National Neuroscience Institute
David Chyi Yeu Low
Duke-NUS Medical School
National Neuroscience Institute
Marija Cvijovic
Chalmers, Matematiska vetenskaper, Tillämpad matematik och statistik
Göteborgs universitet
Wilson Wen Bin Goh
Imperial College London
Nanyang Technological University
Huilin Shao
Universiti Kebangsaan Singapura (NUS)
Agency for Science, Technology and Research (A*STAR)
Nguan Soon Tan
Nanyang Technological University
Stephen Yip
University of British Columbia (UBC)
Anders Martin Jacobsen Skanderup
Agency for Science, Technology and Research (A*STAR)
Carol Tang
National Neuroscience Institute
Duke-NUS Medical School
Patrick Tan
Duke-NUS Medical School
Universiti Kebangsaan Singapura (NUS)
Beng Ti Ang
Duke-NUS Medical School
National Neuroscience Institute
Neuro-Oncology
1522-8517 (ISSN) 15235866 (eISSN)
Vol. In PressÄmneskategorier (SSIF 2025)
Cell- och molekylärbiologi
Cellbiologi
Cancer och onkologi
DOI
10.1093/neuonc/noaf145
PubMed
40518441