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Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma
Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0003-2127-7597
Fourth Mil Med Univ, Dept Neurosurg, Xijing Hosp, Xian 710032, Peoples R China..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0002-0914-6562
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2023 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 25, no 6, p. 1073-1084Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2023. Vol. 25, no 6, p. 1073-1084
Keywords [en]
blood-brain barrier, drug delivery, endothelial cell, glioblastoma, Wnt signaling
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-512762DOI: 10.1093/neuonc/noac288ISI: 000921976900001PubMedID: 36591963OAI: oai:DiVA.org:uu-512762DiVA, id: diva2:1800975
Available from: 2023-09-28 Created: 2023-09-28 Last updated: 2023-09-28Bibliographically approved

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He, LiqunHuang, HuaYang, FanUhrbom, LeneDimberg, Anna

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He, LiqunHuang, HuaYang, FanUhrbom, LeneDimberg, AnnaZhang, Lei
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Science for Life Laboratory, SciLifeLabVascular BiologyDepartment of Immunology, Genetics and PathologyNeurooncology and neurodegeneration
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