| Title: |
Glioportal: a comprehensive transcriptomic resource unveiling ligand-mediated mesenchymal transition in glioblastoma |
| Authors: |
Pang, Qing You; Novera, Wisna; Koh, Lynnette Wei Hsien; Chong, Yuk Kien; Lim, See Wee; Sim, Ngak Leng; Rizzetto, Simone; Liu, Jinyue; Lin, Xuling; Ang, Samantha Ya Lyn; Ker, Justin Rui-Xin; Wan, Kai-Rui; Low, David Chyi Yeu; Cvijovic, Marija; Goh, Wilson Wen Bin; Shao, Huilin; Tan, Nguan Soon; Yip, Stephen; Skanderup, Anders Martin Jacobsen; Tang, Carol; Tan, Patrick; Ang, Beng Ti |
| Contributors: |
Singapore Ministry of Health’s National Medical Research Council; National Research Foundation Singapore |
| Source: |
Neuro-Oncology ; volume 27, issue 11, page 2909-2926 ; ISSN 1522-8517 1523-5866 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2025 |
| Description: |
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-κB 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/neuonc/noaf145 |
| DOI: |
10.1093/neuonc/noaf145/63494721/noaf145.pdf |
| Availability: |
https://doi.org/10.1093/neuonc/noaf145; https://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noaf145/63494721/noaf145.pdf; https://academic.oup.com/neuro-oncology/article-pdf/27/11/2909/63494721/noaf145.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.B5CC64F0 |
| Database: |
BASE |