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LAPTM5-CD40 Crosstalk in Glioblastoma Invasion and Temozolomide Resistance
Anne Berberich1,2, Frederik Bartels1,2, Zili Tang1,3
1German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Abstract:
Background: Glioma therapy is challenged by the diffuse and invasive growth of glioma. Lysosomal protein transmembrane 5 (LAPTM5) was identified as an invasion inhibitor by an in vivo screen for invasion-associated genes. The aim of this study was to decipher the function of LAPTM5 in glioblastoma and its interaction with the CD40 receptor which is intensively evaluated as a target in the therapy of diverse cancers including glioma. Methods: Knockdown of LAPTM5 was performed in different glioma cell lines to analyze the impact on clonogenicity, invasiveness, sensitivity to temozolomide chemotherapy, and tumorigenicity in vitro and in vivo. An expression array was used to elucidate the underlying pathways. CD40 knockdown and overexpression were induced to investigate a potential crosstalk of LAPTM5 and CD40. LAPTM5 and CD40 were correlated with the clinical outcome of glioma patients. Results: Knockdown of LAPTM5 unleashed CD40-mediated NFκB activation, resulting in enhanced invasiveness, clonogenicity, and temozolomide resistance that was overcome by NFκB inhibition. LAPTM5 expression correlated with better overall survival in glioblastoma patients depending on CD40 expression status. Conclusion: We conclude that LAPTM5 conveyed tumor suppression and temozolomide sensitation in CD40-positive glioblastoma through the inhibition of CD40-mediated NFκB activation. Hence, LAPTM5 may provide a potential biomarker for sensitivity to temozolomide in CD40-positive glioblastoma.
Insights
Lysosomal protein transmembrane 5 (LAPTM5) suppresses glioblastoma growth and enhances temozolomide sensitivity by inhibiting CD40-mediated NFκB activation in CD40-positive tumors.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genetics
Background:
- Glioblastoma invasion and diffuse growth pose significant therapeutic challenges.
- Lysosomal protein transmembrane 5 (LAPTM5) was identified as a potential invasion inhibitor.
- Understanding LAPTM5's role in glioblastoma, particularly its interaction with the CD40 receptor, is crucial for targeted therapies.
Purpose of the Study:
- To investigate the function of LAPTM5 in glioblastoma.
- To elucidate the interaction between LAPTM5 and the CD40 receptor in glioblastoma.
- To determine the clinical significance of LAPTM5 and CD40 in glioma patient outcomes.
Main Methods:
- LAPTM5 knockdown in glioma cell lines to assess effects on clonogenicity, invasiveness, and temozolomide sensitivity.
- Expression array analysis to identify underlying molecular pathways.
- CD40 modulation and correlation analysis with clinical data of glioma patients.
Main Results:
- LAPTM5 knockdown activated CD40-mediated NFκB signaling, increasing invasiveness and temozolomide resistance.
- NFκB inhibition reversed the resistance to temozolomide chemotherapy.
- LAPTM5 expression correlated with improved overall survival in glioblastoma patients, contingent on CD40 expression.
Conclusions:
- LAPTM5 exhibits tumor suppressive functions in CD40-positive glioblastoma.
- LAPTM5 enhances temozolomide sensitivity by inhibiting CD40-mediated NFκB activation.
- LAPTM5 may serve as a predictive biomarker for temozolomide response in CD40-positive glioblastoma.
