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Patient- and xenograft-derived organoids recapitulate pediatric brain tumor features and patient treatments.
Brain tumors are the leading cause of cancer-related death in children. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of pediatric brain cancers are limited and hard to establish. We present a protocol that enables efficient generation, expansion, and biobanking of pediatric brain cancer organoids. Utilizing our protocol, we have established patient-derived organoids (PDOs) from ependymomas, medulloblastomas, low-grade glial tumors, and patient-derived xenograft organoids (PDXOs) from medulloblastoma xenografts. PDOs and PDXOs recapitulate histological features, DNA methylation profiles, and intratumor heterogeneity of the tumors from which they were derived. We also showed that PDOs can be xenografted. Most interestingly, when subjected to the same routinely applied therapeutic regimens, PDOs respond similarly to the patients. Taken together, our study highlights the potential of PDOs and PDXOs for research and translational applications for personalized medicine.
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The advancements of organoids push the boundaries of glioblastoma research.
Glioblastoma (GBM) is a malignant tumor of the nervous system, which is difficult to treat due to its strong invasiveness, rapid progression, and poor prognosis. To understand the complex biological behavior of glioblasts and the interaction between tumors and hosts, a new in vitro platform based on human cells is required, which can summarize the complex cellular structure and cell diversity of the human brain, as well as the biological behavior of GBM. Organoids are 3D self-organizing tissues, partially similar to source tissues, which can simulate the structure and physiological functions of organs or tissues in vitro. In this review, we underline the widespread application of different types of GBOs models in GBM pathogenesis, including cells derived, tumor tissues derived, and other co-culture models, as well as their application and shortcomings in the treatment of GBM.
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Modeling brain disorders using transplanted organoids: Beyond the short circuit.
Human cortical organoids transplanted into the somatosensory cortex of rats integrate into the host neural circuits, receive inputs from host cells, and can produce behavioral responses. In a publication in Nature, Revah et al.1 highlight the potential of this platform for modeling circuit defects associated with neurodevelopmental disorders.
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Cerebral Organoids to Study Central Mechanisms of Pain: The Effect of Stem Cell Secretome on Opioid Receptors and Neuroplasticity.
Over 90% of chronic pain (CP) patients receive opioids-based treatments, which led to a public health crisis with lasting impacts on social and economic wellbeing based on opioid addiction. Opioids act through activation of μ (MOR), δ (DOR), and κ (KOR) opioid receptors, which are broadly and differentially distributed throughout the brain. Chronic opioid consumption leads to brain changes such as alterations on neurotransmission, dendritic branching, and spine density, as well as an increase in apoptosis. To overcome opioid-related issues, extensive efforts have been made to search for an alternative treatment. Bioactive molecules secreted by stem cells, collectively known as secretome, have shown a positive impact in different pain models. However, there is a lack of studies on the role of secretome in modulating opioid receptors. By using cerebral organoids (CeO), a self-organized, functional, and multicellular 3D structure that resemble the brain, we were able to identify MOR, DOR, and KOR at different stages of maturation. Treatment with secretome increased MOR expression highlighting a possible role in pain signaling mechanisms. Opioid treatments did not impact the expression of neuronal maturation markers but together with secretome, they increased astrogliogenesis. Opioid-treated organoids presented higher dopamine secretion recapitulating an important physiological event after opioid exposure. This work demonstrates that CeO is an important model system for the study of opioid signaling with potential implications to the understanding of basic mechanisms related to pain physiology.
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ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution.
Embryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+ pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.
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iPSCs-Based Neural 3D Systems: A Multidimensional Approach for Disease Modeling and Drug Discovery.
Induced pluripotent stem cells (iPSCs)-based two-dimensional (2D) protocols have offered invaluable insights into the pathophysiology of neurological diseases. However, these systems are unable to reproduce complex cytoarchitectural features, cell-cell and tissue-tissue interactions like their in vivo counterpart. Three-dimensional (3D)-based culture protocols, though in their infancy, have offered new insights into modeling human diseases. Human neural organoids try to recapitulate the cellular diversity of complex tissues and can be generated from iPSCs to model the pathophysiology of a wide spectrum of pathologies. The engraftment of iPSCs into mice models and the improvement of differentiation protocols towards 3D cultures has enabled the generation of more complex multicellular systems. Consequently, models of neuropsychiatric disorders, infectious diseases, brain cancer and cerebral hypoxic injury can now be investigated from new perspectives. In this review, we consider the advancements made in modeling neuropsychiatric and neurological diseases with iPSC-derived organoids and their potential use to develop new drugs.
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Adenoviral delivery of the CIITA transgene induces T-cell-mediated killing in glioblastoma organoids.
The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell-mediated killing of the tumor through increased activation of the immune system. Patient-based three-dimensional (3D) GB models were infected with a replication-deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC-II) transactivator (CIITA) gene (Ad-CIITA). Successful induction of surface MHC-II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Co-culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA, but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T-cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T-cell-mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediated CIITA delivery to enhance T-cell-mediated immunity against GB.
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Generation of Neural Organoids from Human Embryonic Stem Cells Using the Rotary Cell Culture System: Effects of Microgravity on Neural Progenitor Cell Fate.
Progress in aeronautics and spaceflight technologies requires in parallel further research on how microgravity may affect human tissue. To date, little is known about the effects of microgravity on human development. In this study we used the rotary cell culture system to investigate whether microgravity supports the generation and maintenance of neural organoids derived from human embryonic stem cells (hESCs) as a model of human brain development. Our results show that although neural organoids could be generated and maintained in microgravity conditions, there were changes in expression of rostral-caudal neural patterning genes and cortical markers compared to organoids generated in standard conditions. This phenomenon was also observed in hESC-derived cortical organoids exposed to microgravity for relatively shorter periods. These results are one of the first for analyzing human neurogenesis in a microgravity environment.
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Lineage specification in glioblastoma is regulated by METTL7B.
Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.
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Alcohol use disorder-associated gene FNDC4 alters glutamatergic and GABAergic neurogenesis in neural organoids.
Large-cohort GWAS for alcohol use disorder (AUD) drug treatment outcomes and AUD risk have repeatedly identified genetic loci that are splicing quantitative trait loci for the fibronectin III domain containing 4 (FNDC4) gene in the brain. However, FNDC4 function in the brain and how it might contribute to AUD pathophysiology remain unclear. In the present study, we characterized GWAS loci-associated FNDC4 splice isoforms and demonstrated that FNDC4 alternative splicing results in loss of function for FNDC4. We also investigated FNDC4 function using CRISPR/Cas9 editing and the creation of human induced pluripotent stem cell-derived (iPSC-derived) neural organoids joined with single-nucleus RNA sequencing, a series of studies that showed that FNDC4 KO resulted in a striking shift in the relative proportions of glutamatergic and GABAergic neurons in iPSC-derived forebrain organoids as well as changes in their electrical activity. We further explored a potential mechanism(s) of FNDC4-dependent neurogenesis, and the results suggested a role for FNDC4 in mediating neural cell surface interactions. In summary, this series of experiments indicates that FNDC4 plays a role in regulating cerebral cortical neurogenesis in the brain. This regulation may contribute to the response to AUD pharmacotherapy as well as the effects of alcohol on the brain.