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Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells

Susanto, Evelyn ; Marin Navarro, Ana ; Zhou, Leilei ; Sundström, Anders ; van Bree, Niek ; Stantic, Marina ; Moslem, Mohsen ; Tailor, Jignesh ; Rietdijk, Jonne and Zubillaga, Veronica , et al. (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(33). p.20127-20138
Abstract

Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and... (More)

Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
disease model, medulloblastoma, neural stem cells
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
33
pages
12 pages
publisher
National Academy of Sciences
external identifiers
  • pmid:32747535
  • scopus:85089786767
ISSN
1091-6490
DOI
10.1073/pnas.1920521117
language
English
LU publication?
yes
id
6a32a7a3-6700-4088-a996-e3d42ace406b
date added to LUP
2020-09-07 15:27:40
date last changed
2024-04-17 14:59:10
@article{6a32a7a3-6700-4088-a996-e3d42ace406b,
  abstract     = {{<p>Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.</p>}},
  author       = {{Susanto, Evelyn and Marin Navarro, Ana and Zhou, Leilei and Sundström, Anders and van Bree, Niek and Stantic, Marina and Moslem, Mohsen and Tailor, Jignesh and Rietdijk, Jonne and Zubillaga, Veronica and Hübner, Jens Martin and Weishaupt, Holger and Wolfsberger, Johanna and Alafuzoff, Irina and Nordgren, Ann and Magnaldo, Thierry and Siesjö, Peter and Johnsen, John Inge and Kool, Marcel and Tammimies, Kristiina and Darabi, Anna and Swartling, Fredrik J. and Falk, Anna and Wilhelm, Margareta}},
  issn         = {{1091-6490}},
  keywords     = {{disease model; medulloblastoma; neural stem cells}},
  language     = {{eng}},
  number       = {{33}},
  pages        = {{20127--20138}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells}},
  url          = {{http://dx.doi.org/10.1073/pnas.1920521117}},
  doi          = {{10.1073/pnas.1920521117}},
  volume       = {{117}},
  year         = {{2020}},
}