2. Academic Validation
  3. Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

  • Neuro Oncol. 2023 Jan 2;noac288. doi: 10.1093/neuonc/noac288.
Yuan Xie 1,  Liqun He 2,  Yanyu Zhang 3,  Hua Huang 2,  Fan Yang 2 4,  Min Chao 5,  Haiyan Cao 5,  Jianhao Wang 2 4,  Yaling Li 6,  Lingxue Zhang 1,  Lele Xin 1,  Bing Xiao 1,  Xinxin Shi 1,  Xue Zhang 1,  Jiefu Tang 7,  Lene Uhrbom 3,  Anna Dimberg 2,  Liang Wang 5,  Lei Zhang 1
Affiliations

Affiliations

  • 1 China-Sweden International Joint Research Center for Brain Diseases, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
  • 2 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185, Uppsala, Sweden.
  • 3 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
  • 4 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuro-injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
  • 5 Department of Neurosurgery, Tangdu Hospital of the Fourth Military Medical University, 569 Xinsi Road, Xi'an, 710038, China.
  • 6 Department of Obstetrics and Gynaecology, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710005, China.
  • 7 Trauma Center, First Affiliated Hospital of Hunan University of Medicine, Huaihua, 418000, China.
PMID: 36591963 DOI: 10.1093/neuonc/noac288
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 MSFD2A. 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.

Keywords

Wnt signaling; blood-brain barrier; drug delivery; endothelial cell; glioblastoma.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-17545
    99.92%, PORCN Inhibitor