Biology subjects

Zarodniuk, M.

Publications and source records attributed to Zarodniuk, M..

4 recordsLinked to original sources

bioRxiv2026

Multi-omics and spatial analysis of microgravity-grown glioblastoma organoids reveals superior modeling of advanced disease after long-term spaceflight

Glioblastoma (GBM) is an incurable brain cancer characterized by its highly immunosuppressive tumor microenvironment and aggressive malignant features that resist treatment. To overcome limitations of Earth-based models (sedimentation and disaggregation) and leverage the unique biological effects of space (accelerated disease progression and immune dysregulation), we developed a panel of GBM-myeloid organoids for extended culture on the International Space Station. After 40 days, the spaceflight-grown organoids had more uniform and reproducible morphology compared to identical ground controls. Organoids containing GBM cells + monocytes had increased expression of chronic innate inflammation, adaptive immune activation, and tissue and vascular remodeling-associated genes. There was an increase in organization of gene expression patterns, with mesenchymal-related genes enriched in the core and inflammation-related genes enriched at the periphery, mimicking GBM tumor architecture. Secretomics confirmed the generation of more immunosuppressive organoids, with enrichment of proteins associated with more aggressive disease, including CXCL12 and LOX-1. GBM co-culture organoids thus had enhanced transcriptomic, proteomic, and architectural features when grown in microgravity that are associated with worse patient outcomes from retrospective data. Infrared laser scanning microscopy confirmed spatial chemical gradients for DNA, protein, and lipid species in both space- and terrestrially-grown organoids. In summary, we present not only a novel and superior model of glioblastoma for more relevant basic, mechanistic, and translational research, but also demonstrate methods to acquire high-quality and diverse data from organoids compatible with the unique experimental constraints of biological research in space to help establish a working model for orbital oncology.

cancer biology↗

bioRxiv2025

Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans

Mass effect, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms and poses a significant clinical challenge. In the primary brain tumor glioblastoma (GBM), we have shown previously that compressive solid stress originating from the growing tumor reduces cerebral blood flow, leads to neuronal loss, increased functional impairment, and poor clinical outcomes. However, the direct effects of compression on neurons and the underlying biophysical mechanisms are poorly understood. Here, using multi-scale compression systems and physiologically relevant in vitro and in vivo models, we find that mechanical compression induces neuronal apoptosis and synapse loss, leading to disrupted neural network activity. This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons. We further show that compression triggers AP-1-driven gene expression in glial cells, promoting a neuroinflammatory response. Together, these findings reveal that solid stress directly contributes to neuronal dysfunction and inflammation caused by GBM by activating distinct pathways that can be targeted in future studies for neuroprotection. SIGNIFICANCE STATEMENTGlioblastoma (GBM), the deadliest primary brain tumor in adults, exerts physical forces on surrounding brain tissue as it grows, leading to neuronal damage. However, the molecular mechanisms underlying this process are not well understood. In the present study, by applying multiple model systems, we show that mechanical compression triggers neuronal apoptosis, disrupts synaptic communication between neurons, and reduces neural network activity. We also find that compression activates inflammatory pathways in both neurons and glia, further contributing to neuronal damage. These findings reveal how compression exerted by space-occupying lesions may contribute to patients cognitive and motor impairments and suggest new directions for treatment. This work lays the groundwork for therapies that protect neurons from mechanical injury, with relevance not only to GBM but also other neurological diseases that present with mass effect.

neuroscience↗

bioRxiv2023

Single-cell mechanical analysis reveals viscoelastic similarities between normal and neoplastic brain cells

Understanding cancer cell mechanics allows for the identification of novel disease mechanisms, diagnostic biomarkers, and targeted therapies. In this study, we utilized our previously established fluid shear stress assay to investigate and compare the viscoelastic properties of normal immortalized human astrocytes (IHAs) and invasive human glioblastoma (GBM) cells when subjected to physiological levels of shear stress that are present in the brain microenvironment. We used a parallel-flow microfluidic shear system and a camera-coupled optical microscope to expose single cells to fluid shear stress and monitor the resulting deformation in real-time, respectively. From the video-rate imaging, we fed cell deformation information from digital image correlation into a three-parameter generalized Maxwell model to quantify the nuclear and cytoplasmic viscoelastic properties of single cells. We further quantified actin cytoskeleton density and alignment in IHAs and GBM cells via immunofluorescence microscopy and image analysis techniques. Results from our study show that contrary to the behavior of many extracranial cells, normal and cancerous brain cells do not exhibit significant differences in their viscoelastic behavior. Moreover, we also found that the viscoelastic properties of the nucleus and cytoplasm as well as the actin cytoskeletal densities of both brain cell types are similar. Our work suggests that malignant GBM cells exhibit unique mechanical behaviors not seen in other cancer cell types. These results warrant future study to elucidate the distinct biophysical characteristics of the brain and reveal novel mechanical attributes of GBM and other primary brain tumors.

bioengineering↗

bioRxiv2021

Prioritising Autoimmunity Risk Variants for Functional Analyses by Fine-Mapping Mutations Under Natural Selection

Pathogens imposed selective pressure on humans and shaped genetic variation in immunity genes. This can also be true for a fraction of causal variants implicated in chronic inflammatory disorders. Hence, locating adaptive mutations among candidate variants for these disorders can be a promising way to prioritize and decipher their functional response to microbial stimuli and contribution to pathogenesis. This idea has been discussed for decades, but challenges in locating adaptive SNPs hindered its application in practice. Our study addresses this issue and shows that a fraction of candidate variants for inflammatory conditions evolved under moderate and weak selection regimes (sweeps), and such variants are mappable. Using a novel powerful local-tree-based methodology, we show that 204 out of 593 risk loci for 21 autoimmune disorders contain at least one candidate SNP with strong evidence of selection. More importantly, in 28% of cases, these candidates for causal variants colocalize with SNPs under natural selection that we fine-mapped in this study. Causal SNPs under selection represent promising targets for functional experiments. Such experiments will help decipher molecular events triggered by infectious agents, a likely early event in autoimmunity. Finally, we show that a large fraction (60%) of candidate variants are either hitchhikers or linked with the selected mutation. Our findings, thus, support both hitchhiking and natural selection models, with the latter having important practical implications in medicine.

genetics↗