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Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.
Glioblastoma (GBM) is a highly aggressive adult brain cancer, characterised by poor prognosis and a dismal five-year survival rate. Despite significant knowledge gains in tumour biology, meaningful advances in patient survival remain elusive. The field of neuro-oncology faces many disease obstacles, one being the paucity of faithful models to advance preclinical research and guide personalised medicine approaches. Recent technological developments have permitted the maintenance, expansion and cryopreservation of GBM explant organoid (GBO) tissue. GBOs represent a translational leap forward and are currently the state-of-the-art in 3D in vitro culture system, retaining brain cancer heterogeneity, and transiently maintaining the immune infiltrate and tumour microenvironment (TME). Here, we provide a review of existing brain cancer organoid technologies, in vivo xenograft approaches, evaluate in-detail the key advantages and limitations of this rapidly emerging technology, and consider solutions to overcome these difficulties. GBOs currently hold significant promise, with the potential to emerge as the key translational tool to synergise and enhance next-generation omics efforts and guide personalised medicine approaches for brain cancer patients into the future.
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Assembly of glioblastoma tumoroids and cerebral organoids: a 3D in vitro model for tumor cell invasion.
Glioblastoma (GBM) has a fatal prognosis because of its aggressive and invasive characteristics. Understanding the mechanism of invasion necessitates an elucidation of the relationship between tumor cells and the tumor microenvironment. However, there has been a scarcity of suitable models to investigate this. In this study, we established a glioblastoma-cerebral organoid assembloid (GCOA) model by co-culturing patient-derived GBM tumoroids and human cerebral organoids. Tumor cells from the tumoroids infiltrated the cerebral organoids, mimicking the invasive nature of the parental tumors. Using time-lapse imaging, various invasion patterns of cancer cells within cerebral organoids resembling a normal tissue milieu were monitored. Both single- and collective-cell invasion was captured in real-time. We also confirmed the formation of an intercellular tumor network and tumor-normal-cell interactions. Furthermore, the transcriptomic characterization of GCOAs revealed distinct features of invasive tumor cells. Overall, this study established the GCOA as a three-dimensional (3D) in vitro assembloid model to investigate invasion mechanisms and interactions between tumor cells and their microenvironment.
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Engineering a second brain in a dish.
The utilization of human pluripotent stem cells holds great promise in elucidating principles of developmental biology and applications in personalized and regenerative medicine. Breakthroughs from the last decade have allowed the scientific community to better understand and successfully manipulate human pluripotent stem cells using distinct differentiation strategies into a variety of target tissues. This manipulation relies solely on our understanding of developmental processes occurring in model organisms. The in vitro translation of our developmental knowledge upon stem cells provides a new means to generate specific tissue to understand developmental and disease mechanisms, as well as physiological processes. The generation of an integrated human intestinal tissue is one such example. In this review, we highlight the biological motivation behind the generation of human intestinal organoids. We further describe the integration of an enteric nervous system within the organoid to generate a functional intestine. Forthcoming strategies to add additional complexities to the intestinal tissue so as to better understand how our "second brain" functions within the gut are also discussed. The organoid system offers a promising avenue to understand how the enteric nervous system works and patterns the human intestine during both physiology and disease.
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IQ-MPS Affiliate perspectives on blood-brain barrier microphysiological systems: Progress and challenges ahead.
The endothelial cells of the capillary network in the brain, in conjunction with pericytes and astrocyte end feet, form the blood-brain barrier (BBB). This highly selective cellular barrier helps to protect and maintain brain homeostasis. This barrier function must be circumvented to deliver therapeutics to the brain, a growing need owing to the increasing incidence in neurological disorders in progressively aging populations. Animal models may exhibit species-specific differences in response, ultimately leading to problems with predicting efficacy of treatments in humans, and conventional in vitro models of the BBB face challenges of reproducing cell-cell interactions, the human brain microenvironment, and transporter abundance and type. Microphysiological systems (MPS) and other complex in vitro models aim to address these challenges by combining engineered shear forces coupled with cell biology advancements to create models with greater predictive power, thereby contributing towards the replacement, reduction and/or refinement of animal use (3Rs). Here, we provide an industry perspective on the application of MPS to test drug delivery to the brain, including on newer modalities such as targeted protein degraders, biologics, nanoparticles, and viruses. We also highlight important considerations for MPS model qualification centered on cell sourcing, technological platform, and qualification of functionality. This commentary from members of the Innovation & Quality Microphysiological Systems Affiliate also aims to highlight areas where developers and suppliers can help address gaps in model development.
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Patient-derived organoids predict personalized drug response and reveal alternative therapeutic options in glioblastoma.
Glioblastoma remains a highly aggressive brain tumor with limited treatment options and poor prognosis. Temozolomide (TMZ) is the only approved first-line therapy, but frequent resistance limits its efficacy, highlighting the urgent need for alternative treatments. We establish 18 glioblastoma organoid (GBO) lines that preserve the histopathological and genomic features of the parental tumors, enabling comparison with clinical outcomes. GBO-based drug sensitivity testing (GBO-DST) showed a strong correlation with progression-free survival and outperformed O6-methylguanine-DNA methyltransferase (MGMT) methylation status in predicting TMZ response. Transcriptomic analysis reveals mechanisms of TMZ resistance, including mismatch repair deficiency, elevated MGMT expression, and upregulation of genes associated with axonogenesis and cell adhesion. Using GBO-DST, FDA-approved drug screening identifies regorafenib and lazertinib as effective treatment alternatives. Additionally, lazertinib demonstrated superior efficacy to standard therapies in GBO transplantation mouse model. These findings underscore the potential of GBO-DST as a robust platform for precision oncology in glioblastoma.
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Bridging Toxicological Silos with Organoids: A Systems Approach to Human-Relevant Risk Assessment.
Human-relevant toxic assessment of environmental contaminants remains a critical challenge, as conventional animal models and 2D cell cultures often fail to capture systemic complexity and interindividual variability. Organoid technology, by recapitulating 3D organ architecture, cellular heterogeneity, and donor-specific features, offers a mechanistically rich and ethically superior platform for investigating environmental toxicity. This perspective highlights the use of organoids in developmental and organ-specific toxicity (e.g., liver, brain, and thyroid) as well as patient-derived organoids (PDOs) for personalized susceptibility assessment, enabling the identification of vulnerable cell populations, elucidation of gene-environment interactions, and mechanistic mapping of adverse outcomes. Meanwhile, emerging strategies, including vascularized and unified multiorgan platforms, coculture systems, high-throughput organoid screening, and incorporation with single-cell omics analyses, which enable the mapping of pollutant effects from molecular to tissue and organ levels, were further discussed. Essential challenges, including standardization, scalability, and predictive modeling, are addressed, and we propose that coupling organoid-based approaches with computational and systems-level frameworks can bridge traditional toxicological silos, advancing predictive, mechanistic, and human-relevant environmental health assessment. Collectively, organoid technology is poised to transform environmental toxicology by providing a fully human-relevant, integrative, and predictive platform for chemical risk assessment and regulatory decision-making.
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Long-term region-specific mitochondrial respiration impairment after perinatal asphyxia is prevented by the NAD⁺ donor nicotinamide riboside: A real-time organotypic metabolic profiling approach.
Perinatal asphyxia (PA) is a primary cause of neonatal morbidity, with persistent neurological sequelae, associated with mitochondrial dysfunction and redox imbalance. The lack of experimental approaches for region-specific evaluation of mitochondrial bioenergetics in structurally preserved neural tissues has limited the identification of selective vulnerabilities and redox-based therapeutic targets. Here, we introduce a real-time metabolic profiling strategy that integrates Seahorse XFe96 respirometry with Cytation 5 image-based quality control to quantify mitochondrial respiration and glycolytic flux in organotypic cultures derived from distinct brain regions of neonatal rats exposed to global PA. Using this strategy, we demonstrate that PA induces a profound and region-selective impairment of mitochondrial function, characterized by reduced basal, ATP-linked, maximal, and spare respiratory capacity in the substantia nigra and neostriatum, while neocortical bioenergetics remain largely preserved. These alterations are accompanied by a shift toward glycolysis, reflected by increased extracellular acidification rates and reduced OCR/ECAR ratios. Notably, in vivo administration of the NAD⁺ precursor nicotinamide riboside (0.8 mmol·kg⁻¹, i.p., 1 h after birth) effectively prevented PA-induced mitochondrial respiration deficits, attenuated oxidative stress-induced cell death, and preserved regional neurochemical integrity, particularly within the nigrostriatal neurocircuitry. Together, these findings reveal a heterogeneous mitochondrial redox and bioenergetic vulnerability of the developing brain to perinatal hypoxia. This integrated organotypic-metabolic approach may offer novel opportunities to dissect out region-specific mitochondrial dysfunction and to explore NAD⁺-based therapeutic strategies targeting neonatal brain injury.
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Toward the next generation of vascularized human neural organoids.
Thanks to progress in the development of three-dimensional (3D) culture technologies, human central nervous system (CNS) development and diseases have been gradually deciphered by using organoids derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Selforganized neural organoids (NOs) have been used to mimic morphogenesis and functions of specific organs in vitro. Many NOs have been reproduced in vitro, such as those mimicking the human brain, retina, and spinal cord. However, NOs fail to capitulate to the maturation and complexity of in vivo neural tissues. The persistent issues with current NO cultivation protocols are inadequate oxygen supply and nutrient diffusion due to the absence of vascular networks. In vivo, the developing CNS is interpenetrated by vasculature that not only supplies oxygen and nutrients but also provides a structural template for neuronal growth. To address these deficiencies, recent studies have begun to couple NO culture with bioengineering techniques and methodologies, including genetic engineering, coculture, multidifferentiation, microfluidics and 3D bioprinting, and transplantation, which might promote NO maturation and create more functional NOs. These cutting-edge methods could generate an ever more reliable NO model in vitro for deciphering the codes of human CNS development, disease progression, and translational application. In this review, we will summarize recent technological advances in culture strategies to generate vascularized NOs (vNOs), with a special focus on cerebral- and retinal-organoid models.
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Patient-derived tumor organoids as a platform of precision treatment for malignant brain tumors.
Malignant brain tumors consist of malignancies originated primarily within the brain and the metastatic lesions disseminated from other organs. In spite of intensive studies, malignant brain tumors remain to be a medical challenge. Patient-derived organoid (PDO) can recapitulate the biological features of the primary tumor it was derived from and has emerged as a promising drug-screening model for precision therapy. Here we show a proof-of-concept based on early clinical study entailing the organoids derived from the surgically resected tumors of 26 patients with advanced malignant brain tumors enrolled during December 2020 to October 2021. The tumors included nine glioma patients, one malignant meningioma, one primary lymphoma patient, and 15 brain metastases. The primary tumor sites of the metastases included five from the lungs, three from the breasts, two from the ovaries, two from the colon, one from the testis, one of melanoma origin, and one of chondrosarcoma. Out of the 26 tissues, 13 (50%) organoids were successfully generated with a culture time of about 2 weeks. Among these patients, three were further pursued to have the organoids derived from their tumor tissues tested for the sensitivity to different therapeutic drugs in parallel to their clinical care. Our results showed that the therapeutic effects observed by the organoid models were consistent to the responses of these patients to their treatments. Our study suggests that PDO can recapitulate patient responses in the clinic with high potential of implementation in personalized medicine of malignant brain tumors.
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Matrix composition modulates cancer cell phenotypes and secretions in a blood-brain barrier organ-on-a-chip model: Comparison of collagen and hyaluronic acid.
Recent advances in organ-on-a-chip (OOC) blood-brain barrier (BBB) models for oncology research have revealed key insights into the metastatic cascade. However, in most 3D BBB systems, type I collagen is commonly selected as the brain-side extracellular matrix (ECM) due to its ease of use and affordability. This selection overlooks the native ECM composition of the brain, which is primarily composed of hyaluronan/hyaluronic acid (HyA). Given that the ECM occupies approximately 20% of the brain volume and actively modulates tumor progression, substrate selection is an important yet frequently under-examined component in 3D BBB systems. Using our published blood-brain barrier niche (BBN), we compared HyA and type I collagen matrices to evaluate their impact on cancer cell phenotypes and the tumor microenvironment (TME) to establish which substrate affords the greatest versatility across different lines of investigation. Using a TA DHR-3 rheometer, we examined biophysical variations of these matrices in response to oscillatory shear. We then assessed phenotypic and migratory differences in human breast cancer cells, and their brain-seeking subclones in an ECM of HyA with media versus type I collagen, within our BBN device. Finally, ELISA analysis revealed significant matrix-dependent impact on key chemokine alterations, with collagen matrices promoting CXCL5 and DKK1 secretion across all conditions relative to HyA. We conclude that ECM selection to mimic the patient's brain microenvironment in OOC systems is a critical decision due to inherent substrate differences and either can be appropriate depending on the study goals.