Curated Papers > High-impact authoritative literature on "organoids"

Genetically engineered cerebral organoids model brain tumor formation.

Literature Information

DOI	10.1038/s41592-018-0070-7
PMID	30038414
Journal	Nature methods
Impact Factor	32.1
JCR Quartile	Q1
Publication Year	2018
Times Cited	212
Keywords	Genetically engineered, brain tumor, neoplastic cerebral organoid, CRISPR-Cas9, 3D culture model
Literature Type	Journal Article, Research Support, Non-U.S. Gov't
ISSN	1548-7091
Pages	631-639
Issue	15(8)
Authors	Shan Bian, Marko Repic, Zhenming Guo, Anoop Kavirayani, Thomas Burkard, Joshua A Bagley, Christian Krauditsch, Jürgen A Knoblich

TL;DR

This study introduces a novel 3D organoid model, the neoplastic cerebral organoid (neoCOR), which successfully mimics brain tumorigenesis by incorporating specific oncogenic mutations through advanced genetic techniques. The neoCOR model not only enhances the understanding of tumor biology and invasiveness but also serves as a valuable tool for evaluating drug responses in brain tumor research, addressing the limitations of existing models.

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Genetically engineered · brain tumor · neoplastic cerebral organoid · CRISPR-Cas9 · 3D culture model

Abstract

Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models. Three-dimensional organoid culture models offer innovative possibilities for the modeling of human disease. Here we establish a 3D in vitro model called a neoplastic cerebral organoid (neoCOR), in which we recapitulate brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR-Cas9-mediated mutagenesis. By screening clinically relevant mutations identified in cancer genome projects, we defined mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumor (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable for use in investigations of aspects of tumor biology such as invasiveness, and for evaluation of drug effects in the context of specific DNA aberrations. NeoCORs will provide a valuable complement to the current basic and preclinical models used to study brain tumor biology.

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Primary Questions Addressed

1. How do the specific oncogenic mutations introduced in neoCORs compare to those found in actual brain tumors?
2. What are the potential implications of using neoCORs for personalized medicine in brain tumor treatment?
3. In what ways can neoCORs be utilized to study the interactions between tumor cells and the surrounding brain microenvironment?
4. How do the findings from neoCORs align with current understanding of glioblastoma progression and treatment resistance?
5. What advancements in CRISPR-Cas9 technology could further enhance the modeling of brain tumors using cerebral organoids?

Key Findings

Research Background and Objectives

Brain tumors are among the most lethal cancers, presenting significant challenges due to their genetic heterogeneity and the limitations of existing laboratory models. The objective of this study was to develop a three-dimensional (3D) organoid culture model, termed neoplastic cerebral organoid (neoCOR), to better mimic brain tumorigenesis and facilitate the study of brain tumors, particularly glioblastoma and CNS primitive neuroectodermal tumors (CNS-PNET).

Main Methods/Materials/Experimental Design

The study employed a novel approach combining transposon and CRISPR-Cas9 technologies to introduce specific oncogenic mutations into cerebral organoids. This process allowed for the creation of 3D organoid models that accurately reflect the genetic alterations associated with brain tumors.

Experimental Workflow

Key Results and Findings

• Development of neoCORs: The study successfully established neoCORs that mimic glioblastoma-like and CNS-PNET-like tumors through targeted genetic modifications.
• Mutation Combinations: Specific combinations of mutations were identified that are relevant to tumorigenesis in brain cancers.
• Functional Assessments: The neoCORs demonstrated suitability for studying tumor biology, including invasiveness, and for evaluating the effects of various therapeutic agents in the context of defined DNA aberrations.

Main Conclusions/Significance/Innovativeness

The development of neoCORs represents a significant advancement in the modeling of brain tumors, providing a more accurate and functional platform for studying tumor biology and testing therapeutic interventions. This model offers a promising tool for researchers to explore the complexities of brain tumorigenesis and to develop targeted treatments.

Research Limitations and Future Directions

• Limitations: The study acknowledges potential limitations, such as the need for further validation of neoCORs in vivo and the complexity of fully replicating the tumor microenvironment.
• Future Directions: Future research could focus on refining the neoCOR model to include additional genetic and environmental factors, exploring its use in personalized medicine, and integrating it with other model systems for comprehensive cancer research.

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Literatures Citing This Work

1. From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases. - Matteo Bordoni;Federica Rey;Valentina Fantini;Orietta Pansarasa;Anna Maria Di Giulio;Stephana Carelli;Cristina Cereda - International journal of molecular sciences (2018)
2. Constructing and Deconstructing Cancers using Human Pluripotent Stem Cells and Organoids. - Ryan C Smith;Viviane Tabar - Cell stem cell (2019)
3. Assessment of somatic single-nucleotide variation in brain tissue of cases with schizophrenia. - John F Fullard;Alexander W Charney;Georgios Voloudakis;Andrew V Uzilov;Vahram Haroutunian;Panos Roussos - Translational psychiatry (2019)
4. 3D Bioprinted In Vitro Metastatic Models via Reconstruction of Tumor Microenvironments. - Fanben Meng;Carolyn M Meyer;Daeha Joung;Daniel A Vallera;Michael C McAlpine;Angela Panoskaltsis-Mortari - Advanced materials (Deerfield Beach, Fla.) (2019)
5. Induced pluripotent stem cells in disease modelling and drug discovery. - R Grant Rowe;George Q Daley - Nature reviews. Genetics (2019)
6. Using miniature brain implants in rodents for novel drug discovery. - Ben Waldau - Expert opinion on drug discovery (2019)
7. The Use of Pluripotent Stem Cell-Derived Organoids to Study Extracellular Matrix Development during Neural Degeneration. - Yuanwei Yan;Julie Bejoy;Mark Marzano;Yan Li - Cells (2019)
8. Brain organoids: advances, applications and challenges. - Xuyu Qian;Hongjun Song;Guo-Li Ming - Development (Cambridge, England) (2019)
9. Bioengineering an Artificial Human Blood⁻Brain Barrier in Rodents. - Kimia Kamal;Ben Waldau - Bioengineering (Basel, Switzerland) (2019)
10. Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer. - Ryan C Gimple;Shruti Bhargava;Deobrat Dixit;Jeremy N Rich - Genes & development (2019)

... (202 more literatures)

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