YAP1 gene abnormality drives the occurrence of tube membrane tumor

Backgroundventricular membrane tumor (Ependymoma, EPN) is a central nervous system (CNS) neuroepithelieur tumor, accounting for 10% of all CNS malignancies; It occurs at all ages; Because EPN is a chemotherapy-resistant tumor, surgery plays a major role in the control of local tumorsWith the exception of surgical cut, early postoperative high-dose radiotherapy is the standard method for treating children with unmetepN who are older than 12 months and have not transferred EPNRadiotherapy effectively reduces the risk of EPN recurrence, but the long-term sequelae is also prominent, especially in infant patientsTherefore, there is an urgent need for reliable risk assessment methods and new treatment options for young EPN patientsBased on the progress of molecular intypes of brain tumors in recent years, Kristian WPajtler of the Hopp Children's Oncology Center in Heidelberg, Germany, and others conducted an in-depth study of epN, especially the mechanism selithes of EPN-YAP1 subtypes, and published online in Nature Communications in September 2019research methodschildren's screen (supratentorial, ST) EPN can be divided into two molecular subgroups: ST-EPN-RELA and ST-EPN-YAP1, both of which have high frequency mutationsThe fusion of THE LOWER-stream RELA and C11orf95 in ST-EPN-RELA tumors is commonIn mouse models of neurostem cells (NSCs) or RCAS/tv-a system of the same allogeneic transplant, RELA fusion proteins promote tumor formation originating in the forebrainTumor formation is accompanied by the activation of the NF-B pathway, indicating that inhibiting the signaling pathway is a potential targeted treatmentST-EPN-YAP1 tumors are characterized by the fusion of YAP1 in the Hippo pathway with MAMLD1 or FAM118BIn contrast to ST-EPN-RELA tumors, no other changes such as CDKN2A deficiency or TP53 mutation were observed in ST-EPN-YAP1Yap1-MAMLD1 and YAP1-FAM118B fusion were not reported in other malignant tumors, but YAP1 fusion occurred frequently in EPN, and the researchers concluded that YAP1 may be a carcinogenic initiator of ST-EPN in childrenresultsHippo pathway is regulated by upstream signal transduction proteins, and the transcription alco-factor YAP1 is often limited to cytoplasm to inhibit organ growth and tumor development THE NUCLEAR TRANSLOCATION OF YAP1 PROMOTES STEM CELL PROLIFERATION AND LEADS TO TUMOR FORMATION However, the exact carcinogenic mechanism of YAP1 and YAP1 fusion proteins in EPN is not known The study revealed that YAP1-MAMLD1 fusion is sufficient to drive brain tumors in mice, and that the resulting tumors have similar molecular characteristics to human ventricular membrane tumors The nuclear positioning of the YAP1-MAMLD1 protein is mediated by MAMLD and does not depend on YAP1-Ser127 phosphorylation Immunocoprecipitation-sequencing analysis revealed that, in combination with NFI and TEAD transcription factors, TEAD combined with site mutation or inhibition of NFI could prevent tumors from occurring in mice The above data show that the Hippo pathway transcription factor plays a key role in the carcinogenic driver of YAP1-MAMLD1 Therefore, the researchers concluded that YAP1-MAMLD1 fusion activates the Hippo pathway by collecting TEAD and NFI, leading to the development of ventricular membrane tumors, and that blocking the interaction between transcription factors such as YAP1 fusion protein, NFI, and TEAD can be used as a new target for the treatment of EPN.