This study was completed by Zou Han as a visiting scholar at the Department of Neurological Surgery of University of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh from 2019 to 2023. This study has constructed a system for migration of Purkinje cells in the normally developing cerebellum that are hijacked in the process of medulloblastoma (MB) metastasis and proposed that Dasatinib is significant in the clinical application against MB. Prof. Li Xuejun, Associate Professor Wanggou Siyi and graduate student Xia Shunjin from Department of Neurosurgery of Xiangya Hospital, Prof. Hu Zhongliang and Chief Technician Xie Bin from Department of Pathology, and Attending Physician Liu Fei from Department of Imaging are co-authors. Associate Professor Wu Ming from Department of Neurosurgery, Attending Physician Hu Jian from Department of Hematology, doctoral candidates (including those graduated) Dai Jiacheng, Lin Xuelei, Lin Xiaoyu, Wu Ting, Peng Kang, Li Yanwen, Zhang Yiqian, Wang Jinglin and Xing Dexiu have made great contributions to the study. Prof. Baoli Hu from Department of Neurological Surgery of University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center (UPMC) is the main corresponding author.
MB is the most common embryonal childhood brain tumor, and its metastasis leads to a higher mortality rate. MB cells have been found to metastasize almost exclusively to the spinal and intracranial leptomeninges through cerebrospinal fluid and bloodstream. How MB cells acquire mobility for metastatic dissemination is poorly understood.
Epigenetic characteristics are generally considered to have an important impact on MB. In order to study the overall characteristics of MB, the authors selected the type 3 with the worst prognosis as a representative, and selected SMARCD3 as the only epigenetic-related gene with specific high expression in the type 3 based on bulk RNA-seq, single-cell RNA-seq, proteomics, and clinical survival and metastasis characteristics of a large number of patients. It has been experimentally demonstrated that the RNA and protein expression level of SMARCD3 are correlated and causally related to whether MB patients develop tumor metastasis and whether xenograft mouse tumor models develop tumor metastasis. An in-depth study on downstream signaling reveals that SMARCD3 regulates the DAB1-Reelin signaling pathway through epigenetics, which not only plays a role in the migration of Purkinje cells, but also may be hijacked by MB for metastasis. Further study on upstream signaling reveals that SMARCD3 expression is jointly controlled by EZH2 and NFIX, and cis-regulatory elements(CREs). This system is centered on SMARCD3, whose expression is under the control of EZH2 and NFIX, and CREs, and acts on the DAB1-Reelin signaling pathway through SMARCD3. Moreover, this system acts to timely activate and silence SMARCD3 expression in developing Purkinje cells, thereby controlling the normal migration of Purkinje cells; while in MB, this system is hijacked and also hyperactivated, resulting in SMARCD3 overexpression and causing abnormal MB metastasis. On this basis, the authors proposed that SMARCD3-Reelin-DAB1 signaling pathway may be inhibited to inhibit MB metastasis. After screening drugs that can inhibit the SMARCD3-Reelin-DAB1 signaling pathway, the authors found that Dasatinib was able to significantly inhibit MB metastasis at lower doses, which is instructive for the clinical use of Dasatinib against MB.
CRISPR knockout genes, overexpressed genes, bulk RNA-seq, single-cell RNA-seq, proteomics, ATAC-seq, CUT&RUN, ChIP-seq, HiC, single-cell ATAC-seq, immunofluorescence staining and other techniques were used by the team to study the detailed correlation and causal relationship of developing human cerebellum, mouse cerebellum, human MB, mouse MB and multiple cell lines. Thus, a system hijacked in the MB metastasis and used in normal Purkinje cell migration has been constructed.
Link to the Article:https://www.nature.com/articles/s41556-023-01093-0
The research results of this article are also reported by the Department of Neurological Surgery of University of Pittsburgh School of Medicine and a number of domestic and international institutions.
Link to the article on representative domestic media: https://mp.weixin.qq.com/s/EK9gNXSt-obUP0YhFCPFZQ,
and link to the article on representative foreign media: https://www.neurosurgery.pitt.edu/news/key-culprit-pediatric-brain-cancer-uncovered
