Biology subjects

Burchett, A.

Publications and source records attributed to Burchett, A..

3 recordsLinked to original sources

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↗

bioRxiv2025

Chronic compression drives macrophages toward a pathological pro-tumor state

Macrophages comprise a significant portion of the glioblastoma tumor microenvironment and are essential in promoting immunosuppression and tumor progression. Solid tumors such as glioblastoma generate solid stress as they expand, creating a compressive microenvironment for mechanosensitive immune cells including macrophages. Macrophages are known to respond to various mechanical stimuli but have not yet been studied in the context of chronic compression observed in growing tumors. Here, we used a custom in vitro compression system to elucidate the effects of compressive solid stress on murine macrophages. We found that macrophages have significant morphological, transcriptional, metabolic, and functional responses to compression. These changes corresponded to both canonical pro- and anti-inflammatory macrophage states. The gene expression signatures of compressed macrophages more closely resembled those of glioma-associated macrophages known to be associated with worse patient outcomes. These results indicate that compression alone, independent from tumor cell-derived biochemical factors, may contribute to the pathological tumor-associated macrophage phenotype. This could represent a vicious cycle of tumor immunomechanics and mechano-immunology. Targeting solid stress in tumors or the response to solid stress by macrophages may interrupt this feedback loop to help normalize the tumor immune microenvironment and improve glioblastoma response to immunotherapy.

immunology↗

bioRxiv2024

A Mem-dELISA platform for dual color and ultrasensitive digital detection of colocalized proteins on extracellular vesicles

Accurate, multiplex, and ultrasensitive measurement of different colocalized protein markers on individual tumor-derived extracellular vesicles (EVs) and dimerized proteins with multiple epitopes could provide insights into cancer heterogeneity, therapy management and early diagnostics that cannot be extracted from bulk methods. However, current digital protein assays lack certain features to enable robust colocalization, including multi-color detection capability, large dynamic range, and selectivity against background proteins. Here, we report a lithography-free, inexpensive (< $0.1) and ultrasensitive dual-color Membrane Digital ELISA (Mem-dELISA) platform by using track-etched polycarbonate (PCTE) membranes to overcome these shortcomings. Their through-pores remove air bubbles through wicking before they are sealed on one side by adhesion to form microwells. Immunomagnetic bead-analyte complexes and substrate solution are then loaded into the microwells from the opposite side, with >80% loading efficiency, before sealing with oil. This enables duplex digital protein colorimetric assay with beta galactosidase and alkaline phosphatase enzymes. The platform achieves 5 logs of dynamic range with a limit of detection of 10 aM for both Biotinylated {beta}-galactosidase (B-{beta}G) and Biotin Alkaline Phosphatase Conjugated (B-ALP) proteins. We demonstrate its potential by showing that a higher dosage of paclitaxel suppresses EpCAM-positive EVs but not GPC-1 positive EVs from breast cancer cells, a decline in chemo-resistance that cannot be detected with Western blot analysis of cell lysate. The Mem-dELISA is poised to empower researchers to conduct ultrasensitive, high throughput protein colocalization studies for disease diagnostics, treatment monitoring and biomarker discovery.

cancer biology↗