Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Miller Huang; Jignesh Tailor; Qiqi Zhen; Aaron H. Gillmor; Matthew L. Miller; Holger Weishaupt; Justin Chen; Tina Zheng; Emily K. Nash; Lauren K. McHenry; Zhenyi An; Fubaiyang Ye; Yasuhiro Takashima; James Clarke; Harold Ayetey; Florence M.G. Cavalli; Betty Luu; Branden S. Moriarity; Shirin Ilkhanizadeh; Lukas Chavez; Chunying Yu; Kathreena M. Kurian; Thierry Magnaldo; Nicolas Sevenet; Philipp Koch; Steven M. Pollard; Peter Dirks; Michael P. Snyder; David A. Largaespada; Yoon Jae Cho; Joanna J. Phillips; Fredrik J. Swartling; A. Sorana Morrissy; Marcel Kool; Stefan M. Pfister; Michael D. Taylor; Austin Smith; William A. Weiss

doi:10.1016/j.stem.2019.05.013

Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Miller Huang, Jignesh Tailor, Qiqi Zhen, Aaron H. Gillmor, Matthew L. Miller, Holger Weishaupt, Justin Chen, Tina Zheng, Emily K. Nash, Lauren K. McHenry, Zhenyi An, Fubaiyang Ye, Yasuhiro Takashima, James Clarke, Harold Ayetey, Florence M.G. Cavalli, Betty Luu, Branden S. Moriarity, Shirin Ilkhanizadeh, Lukas ChavezChunying Yu, Kathreena M. Kurian, Thierry Magnaldo, Nicolas Sevenet, Philipp Koch, Steven M. Pollard, Peter Dirks, Michael P. Snyder, David A. Largaespada, Yoon Jae Cho, Joanna J. Phillips, Fredrik J. Swartling, A. Sorana Morrissy, Marcel Kool, Stefan M. Pfister, Michael D. Taylor, Austin Smith, William A. Weiss

Pediatric Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	433-446.e7
Journal	Cell Stem Cell
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2019.05.013
State	Published - Sep 5 2019

Bibliographical note

Funding Information:
We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103 . M.H. was supported by a postdoctoral fellowship ( PF-13-295-01–TBG ) from the American Cancer Society , an Alex’s Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI ( K99CA197484 ). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS ; INSERM ) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01 ), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine , Fondation ARC ( SFI201212055859 ), the Fondation de l'Avenir , the Société Française de Dermatologie , and the Institut National Du Cancer . P.K. was supported by the Hector Stiftung II gGmbH . Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE ( P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom ( G1001028 ). W.A.W. and M.D.T. were supported by a grant from the V Foundation ( T2017-020 ) and by R01CA159859 and R01NS106155 . W.A.W. was supported by the NIH grants R01NS089868 , U01CA217864 , and P30CA82103 ; Brain Tumour Charity grant GN356 ; the Evelyn and Mattie Anderson Chair ; the Ross K. MacNeill Foundation ; the Pediatric Brain Tumor Foundation ; the V Foundation ; and the Samuel G. Waxman Foundation .

Funding Information:
We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103. M.H. was supported by a postdoctoral fellowship (PF-13-295-01–TBG) from the American Cancer Society, an Alex's Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI (K99CA197484). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS; INSERM) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine, Fondation ARC (SFI201212055859), the Fondation de l'Avenir, the Société Française de Dermatologie, and the Institut National Du Cancer. P.K. was supported by the Hector Stiftung II gGmbH. Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE (P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom (G1001028). W.A.W. and M.D.T. were supported by a grant from the V Foundation (T2017-020) and by R01CA159859 and R01NS106155. W.A.W. was supported by the NIH grants R01NS089868, U01CA217864, and P30CA82103; Brain Tumour Charity grant GN356; the Evelyn and Mattie Anderson Chair; the Ross K. MacNeill Foundation; the Pediatric Brain Tumor Foundation; the V Foundation; and the Samuel G. Waxman Foundation. Conceptualization, M.H. J.T. A.S. and W.A.W.; Methodology, M.H. J.T. and P.K.; Writing – Original Draft, M.H. J.T. A.S. and W.A.W.; Writing – Review & Editing, M.H. J.T. A.S. and W.A.W.; Validation: M.H. J.T. Q.Z. A.H.G. H.W. N.S. P.K. A.S.M. and N.S.; Formal Analysis: M.H. J.T. A.H.G. H.W. J.C. F.M.G.C. L.C. J.J.P. and A.S.M.; Investigation: M.H. J.T. Q.Z. M.L.M. T.Z. E.K.N. L.K.M. Z.A. F.Y. Y.T. H.A. B.L. S.I. C.Y. K.M.K. and S.M. Pollard; Resources: Y.T. B.S.M. T.M. N.S. P.K. P.D. M.P.S. D.A.L. Y.J.C. F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Visualization: M.H. J.T. A.H.G. H.W. J.C. and J.J.P.; Supervision: F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Project Administration: M.H. J.T. J.C. A.S. and W.A.W.; Funding Acquisition, M.H. J.T. P.D. A.S. and W.A.W. W.A.W. is a co-founder of StemSynergy Therapeutics.

Publisher Copyright:
© 2019 The Authors

Keywords

SHH
human pluripotent stem cells
medulloblastoma
neuroepithelial stem cells

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2019.05.013

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Huang, M., Tailor, J., Zhen, Q., Gillmor, A. H., Miller, M. L., Weishaupt, H., Chen, J., Zheng, T., Nash, E. K., McHenry, L. K., An, Z., Ye, F., Takashima, Y., Clarke, J., Ayetey, H., Cavalli, F. M. G., Luu, B., Moriarity, B. S., Ilkhanizadeh, S., ... Weiss, W. A. (2019). Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis. Cell Stem Cell, 25(3), 433-446.e7. https://doi.org/10.1016/j.stem.2019.05.013

Huang, M, Tailor, J, Zhen, Q, Gillmor, AH, Miller, ML, Weishaupt, H, Chen, J, Zheng, T, Nash, EK, McHenry, LK, An, Z, Ye, F, Takashima, Y, Clarke, J, Ayetey, H, Cavalli, FMG, Luu, B, Moriarity, BS, Ilkhanizadeh, S, Chavez, L, Yu, C, Kurian, KM, Magnaldo, T, Sevenet, N, Koch, P, Pollard, SM, Dirks, P, Snyder, MP, Largaespada, DA, Cho, YJ, Phillips, JJ, Swartling, FJ, Morrissy, AS, Kool, M, Pfister, SM, Taylor, MD, Smith, A & Weiss, WA 2019, 'Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis', Cell Stem Cell, vol. 25, no. 3, pp. 433-446.e7. https://doi.org/10.1016/j.stem.2019.05.013

@article{d87de59651124db7be95bc042eb64fa4,

title = "Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis",

abstract = "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.",

keywords = "SHH, human pluripotent stem cells, medulloblastoma, neuroepithelial stem cells",

author = "Miller Huang and Jignesh Tailor and Qiqi Zhen and Gillmor, {Aaron H.} and Miller, {Matthew L.} and Holger Weishaupt and Justin Chen and Tina Zheng and Nash, {Emily K.} and McHenry, {Lauren K.} and Zhenyi An and Fubaiyang Ye and Yasuhiro Takashima and James Clarke and Harold Ayetey and Cavalli, {Florence M.G.} and Betty Luu and Moriarity, {Branden S.} and Shirin Ilkhanizadeh and Lukas Chavez and Chunying Yu and Kurian, {Kathreena M.} and Thierry Magnaldo and Nicolas Sevenet and Philipp Koch and Pollard, {Steven M.} and Peter Dirks and Snyder, {Michael P.} and Largaespada, {David A.} and Cho, {Yoon Jae} and Phillips, {Joanna J.} and Swartling, {Fredrik J.} and Morrissy, {A. Sorana} and Marcel Kool and Pfister, {Stefan M.} and Taylor, {Michael D.} and Austin Smith and Weiss, {William A.}",

note = "Funding Information: We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103 . M.H. was supported by a postdoctoral fellowship ( PF-13-295-01–TBG ) from the American Cancer Society , an Alex{\textquoteright}s Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI ( K99CA197484 ). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS ; INSERM ) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01 ), the UNS (Universit{\'e} de Nice Sophia Antipolis) and Association Ren{\'e} Tourraine , Fondation ARC ( SFI201212055859 ), the Fondation de l'Avenir , the Soci{\'e}t{\'e} Fran{\c c}aise de Dermatologie , and the Institut National Du Cancer . P.K. was supported by the Hector Stiftung II gGmbH . Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE ( P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom ( G1001028 ). W.A.W. and M.D.T. were supported by a grant from the V Foundation ( T2017-020 ) and by R01CA159859 and R01NS106155 . W.A.W. was supported by the NIH grants R01NS089868 , U01CA217864 , and P30CA82103 ; Brain Tumour Charity grant GN356 ; the Evelyn and Mattie Anderson Chair ; the Ross K. MacNeill Foundation ; the Pediatric Brain Tumor Foundation ; the V Foundation ; and the Samuel G. Waxman Foundation . Funding Information: We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103. M.H. was supported by a postdoctoral fellowship (PF-13-295-01–TBG) from the American Cancer Society, an Alex's Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI (K99CA197484). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS; INSERM) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01), the UNS (Universit{\'e} de Nice Sophia Antipolis) and Association Ren{\'e} Tourraine, Fondation ARC (SFI201212055859), the Fondation de l'Avenir, the Soci{\'e}t{\'e} Fran{\c c}aise de Dermatologie, and the Institut National Du Cancer. P.K. was supported by the Hector Stiftung II gGmbH. Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE (P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom (G1001028). W.A.W. and M.D.T. were supported by a grant from the V Foundation (T2017-020) and by R01CA159859 and R01NS106155. W.A.W. was supported by the NIH grants R01NS089868, U01CA217864, and P30CA82103; Brain Tumour Charity grant GN356; the Evelyn and Mattie Anderson Chair; the Ross K. MacNeill Foundation; the Pediatric Brain Tumor Foundation; the V Foundation; and the Samuel G. Waxman Foundation. Conceptualization, M.H. J.T. A.S. and W.A.W.; Methodology, M.H. J.T. and P.K.; Writing – Original Draft, M.H. J.T. A.S. and W.A.W.; Writing – Review & Editing, M.H. J.T. A.S. and W.A.W.; Validation: M.H. J.T. Q.Z. A.H.G. H.W. N.S. P.K. A.S.M. and N.S.; Formal Analysis: M.H. J.T. A.H.G. H.W. J.C. F.M.G.C. L.C. J.J.P. and A.S.M.; Investigation: M.H. J.T. Q.Z. M.L.M. T.Z. E.K.N. L.K.M. Z.A. F.Y. Y.T. H.A. B.L. S.I. C.Y. K.M.K. and S.M. Pollard; Resources: Y.T. B.S.M. T.M. N.S. P.K. P.D. M.P.S. D.A.L. Y.J.C. F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Visualization: M.H. J.T. A.H.G. H.W. J.C. and J.J.P.; Supervision: F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Project Administration: M.H. J.T. J.C. A.S. and W.A.W.; Funding Acquisition, M.H. J.T. P.D. A.S. and W.A.W. W.A.W. is a co-founder of StemSynergy Therapeutics. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = sep,

day = "5",

doi = "10.1016/j.stem.2019.05.013",

language = "English (US)",

volume = "25",

pages = "433--446.e7",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "3",

}

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 - Funding Information: We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103 . M.H. was supported by a postdoctoral fellowship ( PF-13-295-01–TBG ) from the American Cancer Society , an Alex’s Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI ( K99CA197484 ). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS ; INSERM ) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01 ), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine , Fondation ARC ( SFI201212055859 ), the Fondation de l'Avenir , the Société Française de Dermatologie , and the Institut National Du Cancer . P.K. was supported by the Hector Stiftung II gGmbH . Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE ( P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom ( G1001028 ). W.A.W. and M.D.T. were supported by a grant from the V Foundation ( T2017-020 ) and by R01CA159859 and R01NS106155 . W.A.W. was supported by the NIH grants R01NS089868 , U01CA217864 , and P30CA82103 ; Brain Tumour Charity grant GN356 ; the Evelyn and Mattie Anderson Chair ; the Ross K. MacNeill Foundation ; the Pediatric Brain Tumor Foundation ; the V Foundation ; and the Samuel G. Waxman Foundation . Funding Information: We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103. M.H. was supported by a postdoctoral fellowship (PF-13-295-01–TBG) from the American Cancer Society, an Alex's Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI (K99CA197484). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS; INSERM) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine, Fondation ARC (SFI201212055859), the Fondation de l'Avenir, the Société Française de Dermatologie, and the Institut National Du Cancer. P.K. was supported by the Hector Stiftung II gGmbH. Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE (P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom (G1001028). W.A.W. and M.D.T. were supported by a grant from the V Foundation (T2017-020) and by R01CA159859 and R01NS106155. W.A.W. was supported by the NIH grants R01NS089868, U01CA217864, and P30CA82103; Brain Tumour Charity grant GN356; the Evelyn and Mattie Anderson Chair; the Ross K. MacNeill Foundation; the Pediatric Brain Tumor Foundation; the V Foundation; and the Samuel G. Waxman Foundation. Conceptualization, M.H. J.T. A.S. and W.A.W.; Methodology, M.H. J.T. and P.K.; Writing – Original Draft, M.H. J.T. A.S. and W.A.W.; Writing – Review & Editing, M.H. J.T. A.S. and W.A.W.; Validation: M.H. J.T. Q.Z. A.H.G. H.W. N.S. P.K. A.S.M. and N.S.; Formal Analysis: M.H. J.T. A.H.G. H.W. J.C. F.M.G.C. L.C. J.J.P. and A.S.M.; Investigation: M.H. J.T. Q.Z. M.L.M. T.Z. E.K.N. L.K.M. Z.A. F.Y. Y.T. H.A. B.L. S.I. C.Y. K.M.K. and S.M. Pollard; Resources: Y.T. B.S.M. T.M. N.S. P.K. P.D. M.P.S. D.A.L. Y.J.C. F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Visualization: M.H. J.T. A.H.G. H.W. J.C. and J.J.P.; Supervision: F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Project Administration: M.H. J.T. J.C. A.S. and W.A.W.; Funding Acquisition, M.H. J.T. P.D. A.S. and W.A.W. W.A.W. is a co-founder of StemSynergy Therapeutics. Publisher Copyright: © 2019 The Authors

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 - SHH

KW - human pluripotent stem cells

KW - medulloblastoma

KW - neuroepithelial stem cells

UR - http://www.scopus.com/inward/record.url?scp=85071524964&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071524964&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2019.05.013

DO - 10.1016/j.stem.2019.05.013

M3 - Article

C2 - 31204176

AN - SCOPUS:85071524964

VL - 25

SP - 433-446.e7

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 3

ER -

Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Abstract

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