Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma
Glioma is the most common intracranial malignancy in adults, with high aggressiveness and high recurrence rates. The inability of drugs to effectively cross the blood-brain barrier is an important reason for poor treatment effectiveness.Led by Zhang Lei, Xie Yuan's research group and Professor Wang Liang's research group of Tangdu Hospital of the Fourth Military Medical University, and the research group of Anna Dimberg and Lene Uhrbom of Uppsala University in Sweden, the company published a report entitled "Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma" in the journal Neuro-Oncology.Using a variety of transgenic mouse models, this study revealed the molecular mechanism by which the Wnt/Mfsd2a signaling pathway regulates endovascular cell endocytosis transport in glioma drug delivery.Neuro-Oncology is a high-level journal in the field of medical sciences, Region 1 of the Chinese Academy of Sciences, impact factor 13.029 (immediate: 14.652). Associate Professor Xie Yuan is the first author, Professor Zhang Lei is the corresponding author, and Shaanxi Normal University is the first signatory unit.
At the single-cell level, the activation of Wnt pathway is related to the expression of blood-brain barrier gene, and the application of Wnt signaling pathway inhibitor LGK974 can significantly improve the delivery of chemotherapy drug temozolomide to tumor tissues, and can synergistically enhance the anti-tumor effect of temozolomide. Transcriptome sequencing analysis of tumor vascular cells found that Wnt signaling pathway blockade could reduce the expression of Mfsd2a, a key molecule of the blood-brain barrier, while increasing the expression of the vascular permeability marker Plvap and the cell vesicle endocytosis transport marker CAV1.

By applying Mfsd2a knockout (MfSD2a-KO) mice and sustainably expressing Mfsd2a Mfsd2a-GOF(Cdh5-CreERT2; ROSA26STOPfloxMfsd2a/TdTomato) mice, found that the Wnt signaling pathways regulate the expression of chemotherapy drug delivery depend on Mfsd2a. In addition, using in vitro blood-brain barrier model, Cav1 knockout (CAV1-KO) mice, and Cav1/Mfsd2a double-knockout mice, it was found that reducing Caveolae-mediated endocytosis can affect the regulatory effect of Mfsd2a knockout on chemotherapy drug delivery. This study reveals that Wnt/Mfsd2a/caveolae-mediated transcytosis axis is an important target to enhance the delivery of chemotherapy drugs, which provides important evidence for the design of therapeutic regimen for glioma.
