Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

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

doi:10.1016/j.stem.2019.05.013

Cited by 62 publications

(73 citation statements)

References 94 publications

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“…However, reduction of DDX3X was further reported to induce self-renewal capability and co-expression of stemness gene signature in liver cancer [53]. Furthermore, the engineered DDX3X mutation in neuroepithelial stem cells isolated from Gorlin syndrome patients induced medulloblastoma in orthotopic transplantation model [58]. Those findings further support the opposite point of view regarding DDX3X-mediated cancer stemness and tumor progression.…”

Section: Ddx3x and Cancer Stemnessmentioning

confidence: 66%

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

Lin

2019

IJMS

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DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-Linked (DDX3X), also known as DDX3, is one of the most widely studied and evolutionarily conserved members of the DEAD-box RNA helicase subfamily, and has been reported to participate in several cytosolic steps of mRNA metabolism. DDX3X facilitates the translation of specific targets via its helicase activity and regulates factors of the translation initiation complex. Emerging evidence illustrates the biological activities of DDX3X beyond its originally identified functions. The nonconventional regulatory effects include acting as a signaling adaptor molecule independent of enzymatic RNA remodeling, and DDX3X exhibits abnormal expression in cancers. DDX3X interacts with specific components to perform both oncogenic and tumor-suppressive roles in modulating tumor proliferation, migration, invasion, drug resistance, and cancer stemness in many types of cancers, indicating the need to unravel the associated molecular mechanisms. In this review article, we summarized and integrated current findings relevant to DDX3X in cancer research fields, cytokines and compounds modulating DDX3X’s functions, and the released transcriptomic information and cancer patient clinical data from public databases. We found evidence for DDX3X having multiple impacts on cancer progression, and evaluated DDX3X expression levels in a pancancer panel and its associations with patient survival in each cancer-type cohort.

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Section: Ddx3x and Cancer Stemnessmentioning

confidence: 66%

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

Lin

2019

IJMS

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“…Recently, a method for differentiating lt-NES towards astroglia has been developed, opening new avenues for the downstream therapeutic use of GMP lt-NES (Lundin et al, 2018). Given its robustness and flexibility, our protocol could be applied for the generation of GMP-compliant neural progenitors that are potentially employable for a variety of neurological therapies, for cell manufacturing scalability studies, drug screenings and other biomedical research applications (Huang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

GMP-grade neural progenitor derivation and differentiation from clinical-grade human embryonic stem cells

Vitillo

Durance

Hewitt

et al. 2020

Preprint

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A major challenge for the clinical use of human pluripotent stem cells is the development of safe, robust and controlled differentiation protocols. Adaptation of research protocols using reagents designated as research-only to those which are suitable for clinical use, often referred to as Good Manufacturing Practice (GMP) reagents, is a crucial and laborious step in the translational pipeline. However, published protocols to assist this process remain very limited. Here we present a new GMP-compliant protocol to derive long-term neuroepithelial stem cell progenitors (lt-NES), which are multipotent, bankable, and karyotypically stable. This protocol resulted in robust and reproducible differentiation of several clinical-grade embryonic stem cells, deposited in the UK Stem Cell Bank, from which we derived lt-NES. Furthermore, GMP-derived lt-NES demonstrated a high neurogenic potential while retaining the ability to be redirected to several neuronal subtypes. Overall, we report the feasibility of derivation and differentiation of clinical grade embryonic stem cell lines into lt-NES under GMP-compliant conditions. Our protocols could be used as a flexible tool to speed up translation-to-clinic of pluripotent stem cells for a variety of neurological therapies or regenerative medicine studies.

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“…Although there have been several models generated from pluripotent cells and genome editing technologies to date 13 , our iHGG models are the first human pluripotent cell derived models that present exact pathognomonic features of GBM, and first to reproduce the heterogeneity of the disease from isogenic cells. These approaches have been applied for models of other brain tumors such as medulloblastoma 34 . Furthermore, recent development of 3D in vitro brain tumor models using cerebral organoid suggests that several different combinations of oncogenic mutations give rise to expanding tumor-like components within organoids, which would approximate in vivo conditions better than conventional cell culture conditions 35 .…”

Section: Discussionmentioning

confidence: 99%

Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development

Koga¹,

Benítez²,

Chaim

et al. 2019

Preprint

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Many current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a new cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that capture authentic cancer pathobiology.Orthotopic engraftment of neural progenitor cells derived from hiPSCs that have been genomeedited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) result in formation of high-grade gliomas. As observed in GBM patient samples, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, and intra-tumor heterogeneity. Further, re-engraftment of primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. Thus, these cancer avatar models provide a platform for a comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation. P.S.M. is co-founder of Pretzel Therapeutics, Inc. He has equity and serves as a consultant for the company. P.S.M. also did a one-time consultation for Abide Therapeutics, Inc. G.W.Y. is co-founder, member of the Board of Directors, equity holder, and paid consultant for Eclipse BioInnovations. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The authors declare no other competing financial interests.

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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Abstract: Highlights d MYCN drives SHH medulloblastoma tumorigenesis in human iPSC-derived NES cells d NES cells from Gorlin syndrome (PTCH1 +/À) iPSCs generate SHH medulloblastoma d Mutation of DDX3X or GSE1 accelerates tumorigenesis in Gorlin NES cells

Cited by 62 publications

References 94 publications

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

GMP-grade neural progenitor derivation and differentiation from clinical-grade human embryonic stem cells

Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development

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