On November 1, 2022, Huang Xi’s Laboratory at the University of Toronto cooperated with the team of Li Xuejun and Wanggou Siyi from the Department of Neurosurgery, Xiangya Hospital of Central South University to publish a research article entitled “Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity” online inNeuron. The study found that in medulloblastoma, processes of Sox2+tumor cells ensheathed capillaries, the process of which depends on the mechanosensitive ion channel Piezo2, and tissue stiffness gradient presented as a function of distance to capillaries. The results show that Sox2+tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension and adhesion to promote cellular process growth and cell surface sequestration of β-Catenin. Piezo2 knockout reverses WNT/β-Catenin signaling states between Sox2+tumor cells and endothelial cells, compromises the blood-tumor barrier (BTB), reduces the quiescence of Sox2+tumor cells, and markedly enhances the medulloblastoma response to chemotherapy. The study also reveals that mechanosensitive tumor cells construct a brand-new BTB in medulloblastoma and elucidates in detail the mechanism by which Piezo2 regulates the chemosensitivity of brain tumors. Prof. Li Xuejun is the co-corresponding author. Attending Physician Wanggou Siyi is one of the first authors, and Xiong Yi, doctoral candidate in the eight-year program at the Department of Neurosurgery, and doctoral candidates Zhao Hongyu, Liu Hongwei and Yang Qi are co-authors.
Taking advantage of a variety of bioinformatics analysis techniques, the team of Li Xuejun and Wanggou Siyi makes great contributions to the study which was supported by the Department of Neurosurgery and the Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research. The team fully compared and analyzed the transcriptome characteristics of Piezo2 wild-type and knockout SHH medulloblastoma mice by single-cell RNA sequencing, and studied the effect of Piezo2 knockout on vascular endothelial cells and Sox2+tumor cells, with the following findings: 1. Piezo2 knockout leads to significant changes in signaling pathways such as “cell junction assembly”, “maintenance of BBB” and “regulation of vascular development” in vascular endothelial cells, thus further confirming the phenotype of disrupted BTB at the transcriptome level; 2. The enhanced vascular permeability of tumor caused by Piezo2 knockout is not resulted from “transcytosis”; 3. SHH mouse model well simulates human medulloblastoma: tumor cells show three states of SHH-A (cell cycle), SHH-B (undifferentiated state) and SHH-C (differentiated state); 4. Sox2+tumor cells mainly show periodic reciprocating shift between SHH-A and SHH-B; 5. Piezo2 knockout can significantly reduce the distribution of Sox2+tumor cells in G0 phase in the migration trajectories of Sox2+tumor cells under G0 and G1 states reconstructed using pseudotime trajectory and RNA velocity techniques, suggesting that Piezo2 knockdown can effectively reduce the quiescence of tumor cells; 6. In Sox2+tumor cells after action by Piezo2 knockout, β-Catenin signaling increases in the nucleus, Axin2 expression is increased and the hallmark of WNT/β-Catenin signaling gene set is globally increased at the transcriptional level.
Besides, the research team analyzed high-throughput multi-omics sequencing data of human medulloblastoma, with the following findings: 1. Piezo2+; Sox2+; GFAP+are mainly present in SHH medulloblastoma, but less expressed in other subtypes; 2. High Piezo2 expression significantly affects the prognosis of SHH medulloblastoma, but not in WNT, Group 3 and Group 4 tumors; 3. Piezo2 also significantly affects the prognosis of pediatric SHH medulloblastoma patients younger than 17 years receiving chemotherapy. These findings provide important clues for studies on the mechanism by which Piezo2 knockdown improves chemosensitivity of brain tumor cells by greatly increasing BTB permeability, and also provide a reference for the possibility of targeting Piezo2 in the treatment of human medulloblastoma.
At present, with the support of Prof. Huang Xi, the team of Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research led by Prof. Li Xuejun has established a comprehensive neuro-oncology research platform integrating clinical diagnosis and treatment, biobank, molecular biology, model organism research (such as drosophila and mice), artificial intelligence and computational vision, bioinformatics, computational biology of cancer and clinical trial research. They have published multiple high-quality cooperative papers in top journals such asNeuron(2 articles),Journal of Experimental Medicine, Nature Metabolism, Science AdvancesandComputational and Structural Biotechnology Journal. The Base extends sincere welcome to cooperation with colleagues dedicated to studies on clinical medicine, basic medicine and translational medicine of brain tumors to jointly address the worldwide problem -- malignant tumors of the central nervous system.
More information:
1. Link to the Article: https://doi.org/10.1016/j.neuron.2022.10.007
2. Report by the Hospital for Sick Children, Toronto: New research rethinks the blood-tumour barrier and identifies novel path to brain cancer treatment | SickKids
