TY - JOUR
T1 - Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
AU - Huang, Miller
AU - Tailor, Jignesh
AU - Zhen, Qiqi
AU - Gillmor, Aaron H
AU - Miller, Matthew L
AU - Weishaupt, Holger
AU - Chen, Justin
AU - Zheng, Tina
AU - Nash, Emily K
AU - McHenry, Lauren K
AU - An, Zhenyi
AU - Ye, Fubaiyang
AU - Takashima, Yasuhiro
AU - Clarke, James
AU - Ayetey, Harold
AU - Cavalli, Florence M G
AU - Luu, Betty
AU - Moriarity, Branden S
AU - Ilkhanizadeh, Shirin
AU - Chavez, Lukas
AU - Yu, Chunying
AU - Kurian, Kathreena M
AU - Magnaldo, Thierry
AU - Sevenet, Nicolas
AU - Koch, Philipp
AU - Pollard, Steven M
AU - Dirks, Peter
AU - Snyder, Michael P
AU - Largaespada, David A
AU - Cho, Yoon Jae
AU - Phillips, Joanna J
AU - Swartling, Fredrik J
AU - Morrissy, A Sorana
AU - Kool, Marcel
AU - Pfister, Stefan M
AU - Taylor, Michael D
AU - Smith, Austin
AU - Weiss, William A
N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2019/9/5
Y1 - 2019/9/5
N2 - Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
AB - Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
KW - Animals
KW - Basal Cell Nevus Syndrome/genetics
KW - Brain Neoplasms/genetics
KW - Carcinogenesis/genetics
KW - DEAD-box RNA Helicases/genetics
KW - Disease Models, Animal
KW - Genetic Engineering
KW - Genetic Predisposition to Disease
KW - Humans
KW - Medulloblastoma/genetics
KW - Mice
KW - Mice, SCID
KW - N-Myc Proto-Oncogene Protein/genetics
KW - Neoplasm Proteins/genetics
KW - Neural Stem Cells/physiology
KW - Neuroepithelial Cells/physiology
KW - Patched-1 Receptor/genetics
KW - Pluripotent Stem Cells/physiology
KW - Stem Cell Transplantation
KW - Transplantation, Heterologous
U2 - 10.1016/j.stem.2019.05.013
DO - 10.1016/j.stem.2019.05.013
M3 - Article
C2 - 31204176
SN - 1934-5909
VL - 25
SP - 433-446.e7
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 3
ER -