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c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma
Open accessAbstract
Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.
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“suggesting that pharmacologic c-Met inhibition might synergise with TMZ treatment and subsequent ICB in CRC.”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [156]
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“Of note, fibroblast-like endothelial cells within the tumour stroma of glioblastoma attenuate the efficacy of TMZ treatment and genetic loss of the hepatocyte growth factor receptor c-Met in endothelial cells synergised with TMZ treatment in a mouse model,156”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [156]
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Self-citation
Metadata
- Authors
- Huang, M., Liu, T., Ma, P., Mitteer, R. A., Zhang, Z., Kim, H. J., Yeo, E., Zhang, D., Cai, P., Li, C., Zhang, L., Zhao, B., Roccograndi, L., O’Rourke, D. M., Dahmane, N., Gong, Y., Koumenis, C., & Fan, Y.
- Affiliations
- University of Pennsylvania (US)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Shanghai University (CN)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-04-04
- Volume
- 126
- Issue
- 5
- Pages
- 1801-1814
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4855929
- OpenAlex
- W2315035682
- Cited by
- 128
- References
- 49
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 13 · 2023: 15 · 2022: 12 · 2021: 15 · 2020: 16 · 2019: 9 · 2018: 13 · 2017: 7 · 2016: 3
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- University of Pennsylvania
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R00HL103792)
- National Cancer Institute (R01CA190415)
- National Institute of Neurological Disorders and Stroke (R01NS094533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- glioblastoma, c-Met, endothelial plasticity, endothelial-to-mesenchymal transition, tumor vascularization, chemoresistance, temozolomide resistance, ETS1, MMP-14, vessel normalization, intratumoral hypoxia, cancer-associated fibroblasts, antivascular therapy
- MeSH terms
- Temozolomide, Animals, Cell Movement, Dacarbazine, Female, Glioblastoma, Humans, Male, Neovascularization, Pathologic, Cell Hypoxia, Mice, Knockout, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Endothelial Cells, Cell Proliferation, Proto-Oncogene Protein c-ets-1, Mice, Matrix Metalloproteinase 14
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