Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

Terada, Yukinori; Jo, Norihide; Arakawa, Yoshiki; Sakakura, Masayoshi; Yamada, Yosuke; Ukai, Tomoyo; Kabata, Mio; Mitsunaga, Kanae; Mineharu, Yohei; Ohta, Sho; Nakagawa, Masato; Miyamoto, Susumu; Yamamoto, Takuya; Yamada, Yoshihiko

doi:10.1016/j.celrep.2019.02.009

Cited by 30 publications

(34 citation statements)

References 47 publications

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“…Their origin from pluripotent progenitors confers a high level of heterogeneity to these tumors, which is often the major hurdle for effective treatment. Recently, it has been demonstrated that by using a human pluripotent stem cell (hPSC)-derived tumor model in various ETs, particularly atypical teratoid/rhabdoid tumors (AT/RT), the presence of an embryonic stem cell (ESC)-like signature is associated with histology and poor prognosis of these tumors (2). These findings suggest that the activation of an early embryonic program in the hPSC progenitors may govern the genetic and epigenetic changes leading to the alteration of the differentiation potential of ETs.…”

Section: Embryonal Tumors and Pluripotent Progenitorsmentioning

confidence: 99%

Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options

2019

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The majority of embryonal tumors or childhood blastomas derive from pluripotent progenitors or fetal stem cells that acquire cancer stem cell (CSC) properties: multipotency, self-renewal ability, metastatic potential, chemoresistance, more pronounced levels of drug transporters, enhanced DNA-damage repair mechanisms, and a quiescent state. Neuroblastoma (NB) is considered a neuroendocrine tumor and is the most common extracranial neoplasm in children. NB pathogenesis has frequently been associated with epigenetic dysregulation and a failure to implement a differentiation program. The origin, characteristics, and isolation of the CSC subpopulation in NB are still incompletely understood, despite the evidence that this cell subset contributes to disease recurrence and acquired resistance to standard therapies. Here, we summarize the literature regarding the isolation and characterization of CSCs in NB over the past decades, from the early recognition of the expression of stem cell factor (SCF) or its receptor c-KIT to more recent studies identifying the ability of G-CSF and STAT3 to support stem cell-like properties in NB cells. Additionally, we review the morphological variants of NB tumors whose recent epigenetic analyses have shed light on the tumor heterogeneity so common in NB. NB-derived mesenchymal stem cells have recently been isolated from primary tumors of NB patients and associated with a pro-tumorigenic role in the tumor microenvironment, enabling immune escape by tumors, and contributing to their invasive and metastatic capabilities. In particular, we will focus on epigenetic reprogramming in the CSC subpopulation in NB and strategies to target CSCs in NB.

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Section: Embryonal Tumors and Pluripotent Progenitorsmentioning

confidence: 99%

Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options

2019

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“…In culture conditions inducing neural differentiation, SMARCB1 was shown to be essential for increased chromatin accessibility at neural differentiation genes and silencing of pluripotency-related super-enhancers (Wang et al, 2017;Langer et al, 2019). Furthermore, SMARCB1null iPSCs that were transplanted into mice were able to generate MRT (Terada et al, 2019). Interestingly, iPSCs that had further progressed to neural progenitor cells (NPCs) generated tumors without rhabdoid features.…”

Section: Pluripotent Stem Cell-derived Cell Linesmentioning

confidence: 99%

“…Recently, the organoid technology was also successfully applied to several pediatric cancers, including embryonal tumors such as MRT and Wilms tumors (Schutgens et al, 2019;Calandrini et al, 2020). The efficient establishment and cryopreservation of tumor organoid models from primary patient tissue allows for the generation of large patient cohorts MYCN overexpression in mouse primary NCCs (Olsen et al, 2017) MYCN/ALK-F1174L overexpression in a mouse NC cell-line (Schulte et al, 2013) Mouse-human chimeras with MYCN overexpression in iPSC-derived hNCCs (Cohen et al, 2020) Engineering human 1p36 deletions in mouse NCCs (García-López et al, 2020) Retinoic acid treatment (Lone et al, 2016;Westerlund et al, 2017) HDAC inhibitors (Hahn et al, 2008;Frumm et al, 2013) EZH2 inhibitors (Chen et al, 2018) MRT Neural crest cells (NCCs) SMARCB1 knockout in iPSCs (Terada et al, 2019) SMARCB1 knockdown in ESCs (Langer et al, 2019) SMARCB1 knockout in cerebellar organoids (Parisian et al, 2020) HDAC inhibitors (Muscat et al, 2016) EZH2 inhibitors (Knutson et al, 2013) Medulloblastoma Neural progenitor cells c-MYC overexpression in cerebellar organoids (Ballabio et al, 2020) MYCN overexpression in neuroepithelial stem cells (Huang et al, 2019) Retinoic acid treatment (Patties et al, 2016) EZH2 inhibitors (Cheng et al, 2020) SHH inhibitors (Ocasio et al, 2019) BET-bromodomain inhibitors (Bandopadhayay et al, 2019) DIPG Oligodendrocyte precursor cells H3K27M mutations in hESC derived NPCs (Funato et al, 2014) ACVR1 mutations in neurospheres (Hoeman et al, 2019) HDAC inhibitors (Anastas et al, 2019) BET-bromodomain inhibitors (Mohammad et al, 2017) Retinoblastoma Cone precursor cells RB1 depletion in fetal retinal cell cultures (Xu et al, 2014) RB1 depletion in hESC derived retinal organoids (Liu H. et al, 2020;…”

Section: Reverse Tumor Modeling and Differentiation Therapymentioning

confidence: 99%

In vitro Modeling of Embryonal Tumors

Custers

Paassen

Drost

2021

Front. Cell Dev. Biol.

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A subset of pediatric tumors affects very young children and are thought to arise during fetal life. A common theme is that these embryonal tumors hijack developmental programs, causing a block in differentiation and, as a consequence, unrestricted proliferation. Embryonal tumors, therefore typically maintain an embryonic gene signature not found in their differentiated progeny. Still, the processes underpinning malignant transformation remain largely unknown, which is hampering therapeutic innovation. To gain more insight into these processes, in vitro and in vivo research models are indispensable. However, embryonic development is an extremely dynamic process with continuously changing cellular identities, making it challenging to define cells-of-origin. This is crucial for the development of representative models, as targeting the wrong cell or targeting a cell within an incorrect developmental time window can result in completely different phenotypes. Recent innovations in in vitro cell models may provide more versatile platforms to study embryonal tumors in a scalable manner. In this review, we outline different in vitro models that can be explored to study embryonal tumorigenesis and for therapy development.

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“…To overcome the laborious and time-consuming processes of generating GEM models, Zuckermann 41) Huang et al 43) Terada et al 45) Koga et al 47) Feasibility in experimental standardization in isogenic background Enabling human tumor biology investigation…”

Section: Spontaneous Mouse Brain Tumor Models Using Genome Engineeringmentioning

confidence: 99%

“…disrupted SMARCB1 , which is recurrently affected in atypical teratoid rhabdoid tumors (AT/RT), 44) to model this malignant pediatric brain cancer. 45) This study presented a potential use of brain tumor cells derived from genetically engineered human iPSCs for drug screening.…”

Section: Brain Tumor Models Derived From Genome-engineered Human Stemmentioning

confidence: 99%

Genome Engineering Evolves Brain Tumor Modeling

Koga

Chen

Furnari

2020

Neurol. Med. Chir.(Tokyo)

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Genome engineering using programmable nucleases such as transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeat-associated protein nine facilitated the introduction of genetic alterations at specific genomic sites in various cell types. These tools have been applied to cancer modeling to understand the pathogenic effects of the growing catalog of mutations found in human cancers. Pertaining to brain tumors, neural progenitor cells derived from human induced pluripotent stem cells (iPSCs) engineered with different combinations of genetic driver mutations observed in distinct molecular subtypes of glioblastomas, the most common form of primary brain cancer in adults, give rise to brain tumors when engrafted orthotopically in mice. These glioblastoma models recapitulate the transcriptomic signature of each molecular subtype and authentically resemble pathobiology of glioblastoma, including inter-and intra-tumor heterogeneity, chromosomal aberrations, and extrachromosomal DNA amplifications. Similar engineering with genetic mutations found in medulloblastoma and atypical teratoid rhabdoid tumors in iPSCs have led to genetically trackable models that bear clinical relevance to these pediatric brain tumors. These models have contributed to improved comprehension of the genetic causation of tumorigenesis and offered a novel platform for therapeutic discovery. Studied in the context of three-dimensional cerebral organoids, these models have aided in the study of tumor invasion as well as therapeutic responses. In summary, modeling brain tumors through genome engineering enables not only the establishment of authentic tumor avatars driven by bona fide genetic mutations observed in patient samples but also facilitates functional investigations of particular genetic alterations in an otherwise isogenic background.

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Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

Cited by 30 publications

References 47 publications

Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options

Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options

In vitro Modeling of Embryonal Tumors

Genome Engineering Evolves Brain Tumor Modeling

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