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Targeting the Cargo Receptor TMED9 as a Therapeutic Strategy Against Brain Tumors
Alaa Daoud Sarsour1,2, Sara Kinstlinger1, Rephael Nizar1,2
1The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.
Cells
|June 11, 2025
Summary
Targeting TMED9, a protein linked to aggressive brain tumors, shows promise. Inhibiting TMED9 in glioblastoma stem cells and other glioma cells reduced tumor growth and improved treatment outcomes, even with existing therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Glioblastoma is an aggressive brain cancer with poor prognosis.
- TMED proteins, particularly TMED9, are implicated in cancer progression.
- TMED9 functions as a cargo receptor in the secretory pathway, influencing protein trafficking.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting TMED9 in glioma models.
- To determine the role of TMED9 in glioblastoma stem cell self-renewal and migration.
- To evaluate the efficacy of TMED9 inhibition alone and in combination with temozolomide.
Main Methods:
- Analysis of TMED9 expression in glioma patient samples.
- Utilizing patient-derived glioma tumor and stem cells.
- Employing genetic and pharmacologic inhibition of TMED9 using the small molecule BRD4780.
- Assessing cell viability, migration, proliferation, and stemness.
- Testing combination therapy with temozolomide and evaluating pediatric glioma models.
Main Results:
- TMED9 is upregulated in glioma and associated with poor survival.
- TMED9 is highly expressed in glioma stem cells, promoting their self-renewal and migration.
- BRD4780 effectively reduced TMED9 levels, decreasing glioma stem cell viability, migration, and stemness.
- BRD4780 inhibited proliferation and migration of differentiated glioma cells.
- Combination therapy with temozolomide enhanced anti-tumor response.
- TMED9 inhibition was effective in pediatric glioma cells.
Conclusions:
- TMED9 inhibition is a promising therapeutic strategy for brain tumors, particularly targeting the cancer stem cell population.
- TMED9 plays a critical role in glioma tumorigenesis and aggressiveness.
- BRD4780 demonstrates significant anti-tumor activity and potential for combination therapy.
- TMED9 targeting offers broad applicability across different glioma cell types and pediatric cancers.
