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TMZ regulates GBM stemness via MMP14-DLL4-Notch3 pathway
Ilya V Ulasov1, Olja Mijanovic1, Solomiia Savchuk2
1Institute of Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia.
International Journal of Cancer
|August 24, 2019
Summary
Temozolomide treatment in glioblastoma (GBM) promotes nuclear MMP14 translocation, leading to DLL4 release. This process enhances glioma stemness and tumor recurrence.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with high recurrence rates after standard treatments.
- Understanding resistance mechanisms is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of matrix metalloproteinase 14 (MMP14) in mediating glioblastoma resistance.
- To elucidate the molecular mechanisms linking MMP14 to glioma stemness and treatment resistance.
Main Methods:
- Utilized patient-derived xenograft (PDX) GBM models and glioma cell lines.
- Characterized MMP14 expression and localization post-temozolomide (TMZ) treatment.
- Employed Kiloplex ELISA arrays and functional studies involving delta-like canonical notch ligand 4 (DLL4) and Notch3 signaling.
Main Results:
- Temozolomide treatment induced nuclear translocation of MMP14.
- Nuclear MMP14 translocation was followed by extracellular release of DLL4.
- DLL4 stimulated Notch3 cleavage, nuclear translocation, and enhanced glioma stemness and sphere-forming capacity.
Conclusions:
- MMP14 plays a critical role in mediating glioblastoma resistance to temozolomide.
- The MMP14-DLL4-Notch3 axis regulates glioma stemness, offering potential therapeutic targets.
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