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

Evelyn Susanto; Ana Marin Navarro; Leilei Zhou; Anders Sundström; Niek van Bree; Marina Stantic; Mohsen Moslem; Jignesh Tailor; Jonne Rietdijk; Veronica Zubillaga; Jens Martin Hübner; Holger Weishaupt; Johanna Wolfsberger; Irina Alafuzoff; Ann Nordgren; Thierry Magnaldo; Peter Siesjö; John Inge Johnsen; Marcel Kool; Kristiina Tammimies; Anna Darabi; Fredrik J. Swartling; Anna Falk; Margareta Wilhelm

doi:10.1073/PNAS.1920521117

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

Evelyn Susanto, Ana Marin Navarro, Leilei Zhou, Anders Sundström, Niek van Bree, Marina Stantic, Mohsen Moslem, Jignesh Tailor, Jonne Rietdijk, Veronica Zubillaga, Jens Martin Hübner, Holger Weishaupt, Johanna Wolfsberger, Irina Alafuzoff, Ann Nordgren, Thierry Magnaldo, Peter Siesjö, John Inge Johnsen, Marcel Kool, Kristiina TammimiesAnna Darabi, Fredrik J. Swartling, Anna Falk, Margareta Wilhelm

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	20127-20138
Aantal pagina's	12
Tijdschrift	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Nummer van het tijdschrift	33
DOI's	https://doi.org/10.1073/PNAS.1920521117
Status	Gepubliceerd - aug. 2020
Extern gepubliceerd	Ja

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Susanto, E., Navarro, A. M., Zhou, L., Sundström, A., van Bree, N., Stantic, M., Moslem, M., Tailor, J., Rietdijk, J., Zubillaga, V., Hübner, J. M., Weishaupt, H., Wolfsberger, J., Alafuzoff, I., Nordgren, A., Magnaldo, T., Siesjö, P., Johnsen, J. I., Kool, M., ... Wilhelm, M. (2020). Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells. Proceedings of the National Academy of Sciences of the United States of America, 117(33), 20127-20138. https://doi.org/10.1073/PNAS.1920521117

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title = "Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells",

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 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.",

keywords = "Disease model, Medulloblastoma, Neural stem cells",

author = "Evelyn Susanto and Navarro, {Ana Marin} and Leilei Zhou and Anders Sundstr{\"o}m and {van Bree}, Niek and Marina Stantic and Mohsen Moslem and Jignesh Tailor and Jonne Rietdijk and Veronica Zubillaga and H{\"u}bner, {Jens Martin} and Holger Weishaupt and Johanna Wolfsberger and Irina Alafuzoff and Ann Nordgren and Thierry Magnaldo and Peter Siesj{\"o} and Johnsen, {John Inge} and Marcel Kool and Kristiina Tammimies and Anna Darabi and Swartling, {Fredrik J.} and Anna Falk and Margareta Wilhelm",

year = "2020",

month = aug,

doi = "10.1073/PNAS.1920521117",

language = "English",

volume = "117",

pages = "20127--20138",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "33",

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Susanto, E, Navarro, AM, Zhou, L, Sundström, A, van Bree, N, Stantic, M, Moslem, M, Tailor, J, Rietdijk, J, Zubillaga, V, Hübner, JM, Weishaupt, H, Wolfsberger, J, Alafuzoff, I, Nordgren, A, Magnaldo, T, Siesjö, P, Johnsen, JI, Kool, M, Tammimies, K, Darabi, A, Swartling, FJ, Falk, A & Wilhelm, M 2020, 'Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, nr. 33, blz. 20127-20138. https://doi.org/10.1073/PNAS.1920521117

TY - JOUR

T1 - Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells

AU - Susanto, Evelyn

AU - Navarro, Ana Marin

AU - Zhou, Leilei

AU - Sundström, Anders

AU - van Bree, Niek

AU - Stantic, Marina

AU - Moslem, Mohsen

AU - Tailor, Jignesh

AU - Rietdijk, Jonne

AU - Zubillaga, Veronica

AU - Hübner, Jens Martin

AU - Weishaupt, Holger

AU - Wolfsberger, Johanna

AU - Alafuzoff, Irina

AU - Nordgren, Ann

AU - Magnaldo, Thierry

AU - Siesjö, Peter

AU - Johnsen, John Inge

AU - Kool, Marcel

AU - Tammimies, Kristiina

AU - Darabi, Anna

AU - Swartling, Fredrik J.

AU - Falk, Anna

AU - Wilhelm, Margareta

PY - 2020/8

Y1 - 2020/8

N2 - 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.

AB - 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.

KW - Disease model

KW - Medulloblastoma

KW - Neural stem cells

UR - http://www.scopus.com/inward/record.url?scp=85089786767&partnerID=8YFLogxK

U2 - 10.1073/PNAS.1920521117

DO - 10.1073/PNAS.1920521117

M3 - Article

C2 - 32747535

AN - SCOPUS:85089786767

SN - 0027-8424

VL - 117

SP - 20127

EP - 20138

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 33

ER -

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

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