title: Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells.
abstract: Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Actin cytoskeleton regulator Arp2/3 complex stimulates glioma cell motility and migration, and thus triggers tumor invasion. However, little is known regarding the role of actin cytoskeleton in maintaining the stem cell phenotype. Here, we showed that Arp2/3 complex improved stem cell phenotype maintenance through sustaining the activated Notch signaling. ShRNA targeting Notch ligand Delta-like 1 (DLL1) decreased CD133 and Nestin expression, and impaired the self-renewal ability of CD133+ U87-MG and U251-MG glioma cells, indicating DLL1/Notch1 signaling promoted stem cell phenotype maintenance. Interestingly, inhibiting Arp2/3 complex also induced the similar effect of shDLL1. Silencing DLL1 in the Arp2/3 inhibited CD133+ cells did not further abrogate the stem cell phenotype, suggesting DLL1 function requires Arp2/3 complex in glioma initiating cells (GICs). However, exogenous soluble DLL1 (sDLL1) instead of endogenous DLL1 rescued the Arp2/3 inhibition-induced stem cell phenotype suppression. The underlying mechanism was that Arp2/3 inhibition impeded DLL1 vesicular transport from cytoplasm to cell membrane, which resulted in DLL1 unable to activate Notch pathway. Furthermore, we illustrated that Arp2/3 inhibition abolished the tumorigenicity of CD133+ U87-MG neurosphere cells in the intracranial model. These findings suggested that cytoskeleton maintained the stem cell phenotype in GBM, which provide novel therapeutic strategy that anti-invasive targeted therapies may help eliminate GICs.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Long
authors.initials: L
authors.lastname: Hai
authors.affiliation: Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Xingchen
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Neurological Institute, Tianjin, 300052, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Yang
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D051376:Actin-Related Protein 2-3 Complex; D015415:Biomarkers; D051881:Receptor, Notch1
keywords: Arp2/3 complex; Notch signaling; cytoskeleton; delta-like1; glioma initiating cell