Artikel
Inhibition of the discoidin receptor 1 DDR1 improves efficacy of adjuvant therapy in glioblastoma
Die Inhibition des Discoidin-Rezeptors DDR1 verbessert die Effektivität der adjuvanten Therapie in Glioblastomen
Suche in Medline nach
Autoren
-
Anne Vehlow
- Technische Universität Dresden, Onkologie, Dresden, Deutschland
-
Erik Klapproth
- Technische Universität Dresden, Onkologie, Dresden, Deutschland
-
Ricarda Hannen
- Philipps-Universität Marburg, Neurochirurgie, Marburg, Deutschland
-
Achim Temme
- Technische Universität Dresden, Klinik für Neurochirurgie, Dresden, Deutschland
-
Christopher Nimsky
- Philipps-Universität Marburg, Klinik für Neurochirurgie, Marburg, Deutschland
-
Nils Cordes
- Technische Universität Dresden, Onkologie, Dresden, Deutschland
-
Jörg-Walter Bartsch
- Philipps-Universität Marburg, Neurochirurgie, Marburg, Deutschland
| Veröffentlicht: | 26. Juni 2020 |
|---|
Gliederung
Text
Objective: A major obstacle to adjuvant GBM therapy using radiatio and temozolomide (TMZ) is the formation of drug- and radiation-resistant GBM stem cells (GSCs). Interestingly, GSCs utilize collagen signalling to regulate TMZ resistance. In order to understand this process in detail, a study was initiated to reveal the mechanisms of radiochemoresistance based on signalling by the Discoidin Domain Receptor (DDR1), a receptor tyrosine kinase that is activated by tumor cell derived collagen.
Methods: Expression of DDR1 in GSCs was evaluated in GBM patients by immunostaining using antibodies against DDR1 and the stem cell markers nestin, Sox2, and Musashi. Spheres derived from GSCs were irradiated (0-6 Gy) and TMZ (0.2-10 mM) treated ± DDR inhibitor (DDR1i). Furthermore, GSCs were implanted in nude mice and tumors were co-treated with TMZ±DDR1i. The interaction of DDR1 with intracellular signalling pathways was analyzed by co-immunoprecipitation in U343MG cells.
Results: We demonstrated that DDR1 is highly enriched in GSCs with expression levels negatively correlated to patient survival (n=20, significance p=0.08). The inhibition of DDR1 in combination with radiochemotherapy using TMZ in GSCs enhances sensitivity and prolongs survival of mice better tjhan conventional therapy. Mechanically, we demonstrated that DDR1 forms an intracellular complex with the proteins 14-3-3 and Beclin1 to keep PI3K/AKT/mTOR signalling activated thereby triggering cell proliferation and survival. In contrast,the inhibition of DDR1 prevents 14-3-3 and Beclin-1 from binding to DDR1 and leads to alternative complexes of Beclin-1 with Vps 34 and Atg 14 to initiate autophagy that results in sensitization of GSCs to radiochemotherapy.
Conclusion: Here we unraveled a novel mechanism of radiochemoresistance. GBM stem cells utilise tumor-derived collagen as an extracellular trigger to suppress cytotoxic signals by DDR1 receptor signalling. In conclusion, these findings provide a rationale for improving radiochemotherapy in GBM patients by combinatorial therapies involving the inhibition of DDR1.
