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Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma

Xie, Yuan, He, Liqun, Zhang, Yanyu, Huang, Hua, Yang, Fan, Chao, Min, Cao, Haiyan, Wang, Jianhao, Li, Yaling, Zhang, Lingxue, Xin, Lele, Xiao, Bing, Shi, Xinxin, Zhang, Xue, Tang, Jiefu, Uhrbom, Lene, Dimberg, Anna, Wang, Liang, Zhang, Lei·2023·Neuro-Oncology
DOI 10.1093/neuonc/noac288
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Abstract

Background: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. Methods: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms. Results: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. Conclusions: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.

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Metadata

Authors
Xie, Y., He, L., Zhang, Y., Huang, H., Yang, F., Chao, M., Cao, H., Wang, J., Li, Y., Zhang, L., Xin, L., Xiao, B., Shi, X., Zhang, X., Tang, J., Uhrbom, L., Dimberg, A., Wang, L., & Zhang, L.
Venue
Neuro-Oncology
Publisher
Oxford University Press (OUP)
Published
2023-01-02
Volume
25
Issue
6
Pages
1073-1084
ISSN
  • 1522-8517
  • 1523-5866
DOI
10.1093/neuonc/noac288
Cited by
55
References
4
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Funders
  • National Natural Science Foundation of China
  • Swedish Foundation for International Cooperation in Research and Higher Education (STINT) Mobility Program (81911530166, 81702489, 82002659, 81870978, 81772661)
  • Swedish Cancer Foundation
  • Swedish Science Council
  • Natural Science Foundation of Shaanxi Province (2021KW-46, 2020JZ-30)
  • Natural Science Foundation of Hunan Province (2022JJ50300)

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