Biology subjects

Ceberg, C.

Publications and source records attributed to Ceberg, C..

5 recordsLinked to original sources

bioRxiv2025

Coevolution of neoplastic and non-neoplastic reactive astrocyte states converges on mesenchymal-like and injury-response programs during murine glioblastoma progression and post-radiotherapy recurrence

Glioblastomas initially respond to radiotherapy but invariably recur, often within high-dose radiation treatment fields. Although stromal radiation responses are incompletely understood, evidence suggests that the tumor microenvironment becomes tumor-supportive after therapy. Using a genetically engineered glioblastoma mouse model, we profiled healthy brain, primary tumors, and post-radiotherapy recurrences with single-cell and spatial transcriptomics and immunohistochemistry. Across 13 non-neoplastic cell types and 10 tumor cell states, we mapped transcriptional adaptations accompanying progression from healthy brain to primary and recurrent glioblastoma. We identified distinct astrocyte states linked to disease stage, including reactive non-neoplastic astrocytes and tumor cells adopting reactive astrocyte-like phenotypes. Reactive astrocyte-like tumor cells with mesenchymal and injury-response signatures were enriched after radiotherapy and persisted in recurrent tumors. Receptor-ligand interactions between reactive astrocytes and tumor cells included known and putative drivers of aggressiveness. These findings highlight convergent reactive astrocyte programs in astrocytes and tumor cells as potential mediators of glioblastoma radioresistance.

cancer biology↗

bioRxiv2025

Restriction-weighted q-space trajectory imaging (ResQ): Toward mapping diffusion time effects with tensor-valued diffusion encoding in human prostate cancer xenografts

PurposeTensor-valued diffusion encoding employs gradient waveforms that enable unique sensitivity to microstructural features of tissue, but the interpretation of signal and parameters may be confounded by diffusion-time dependence. We introduce a framework for restriction-weighted q-space trajectory imaging (ResQ) that incorporates diffusion-time effects via the restriction-weighting tensor, and we evaluate it in a longitudinal study of prostate cancer xenografts treated by external radiotherapy. MethodsWe proposed a novel gradient waveform design for tensor-valued encoding with controlled restriction weighting and applied a set of four waveforms at a 9.4 T preclinical MRI system. Mice were inoculated with human prostate cancer cells (LNCaP) and assigned to groups that were untreated controls or treated by external beam irradiation. ResQ produced parameters that describes the diffusion process in terms of the mean diffusivity (D), isotropic diffusional variance (VDi), and microscopic diffusion anisotropy (VDa) as well as their diffusion-time dependence ({Delta}D, {Delta}VDi, {Delta}VDa). Analyses were performed to characterize parameters longitudinally and across groups. To highlight the consequences of ignoring restriction effects, we compared ResQ to analogous parameters estimated by q-space trajectory imaging (QTI). ResultsResQ revealed clear diffusion-time dependence across all tumors, with significant longitudinal differences between treated and untreated groups, most prominent in D, {Delta}D, and VDi. The ResQ signal representation captured the signal dynamics, whereas QTI did not. Neglecting diffusion-time dependence in QTI led to substantial parameter bias, most notably a pronounced overestimation of microscopic diffusion anisotropy. ConclusionDiffusion-time effects are non-negligible in prostate cancer and must be considered when using tensor-valued diffusion encoding. The ResQ framework enables controlled restriction weighting and improved interpretability of diffusion MRI parameters compared to approaches that ignore the effects of restriction. This provides a more principled approach for tensor-valued diffusion encoding and may enable novel imaging biomarkers that disentangle diffusivity, isotropic diffusional variance, microscopic anisotropy, and their diffusion-time dependence.

biophysics↗

bioRxiv2025

Phenotypic Screening Identifies Flunarizine as an Inhibitor of Radiotherapy-Induced Astrocyte Reactivity with Therapeutic Potential in Glioblastoma

Radiotherapy is part of the standard-of-care for glioblastoma, yet tumors invariably recur as incurable lesions post-treatment. Recent studies suggest that radiation-induced astrocyte reactivity fosters a tumor-supportive environment, however effective strategies targeting reactive astrocyte phenotypes are lacking. Using a novel image-based assay, we screened over 1,700 small molecule compounds, identifying 29 that inhibit radiation-induced astrocyte reactivity in human astrocytes. Among these, Flunarizine, a calcium-entry blocker approved for migraine treatment, significantly reduced astrocyte reactivity in vitro and in vivo. In a genetically engineered glioblastoma mouse model, combining Flunarizine with radiotherapy markedly improved survival without affecting unirradiated controls, indicating specificity for a radiation-induced phenotype. Mechanistically, Flunarizine inhibited radiation-induced fibrosis in vivo and directly suppressed astrocytic TGF-beta activation in vitro. Notably, Flunarizine treatment had no direct effect on primary glioblastoma cells, emphasizing its microenvironmental specificity. In conclusion, we identified Flunarizine as a promising repurposed compound capable of effectively mitigating radiation-induced astrocyte reactivity and delaying glioblastoma recurrence. This approach offers a viable therapeutic strategy to enhance current glioblastoma treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/664538v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@d4d0d6org.highwire.dtl.DTLVardef@1dac551org.highwire.dtl.DTLVardef@1d071ccorg.highwire.dtl.DTLVardef@1df1a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Aberrant Neuronal Synchronization Associated with Cognitive Deficits in a Rodent Model of Childhood Cranial Irradiation

Cranial radiation can be a life-saving intervention in pediatric brain cancer therapy but often results in debilitating cognitive decline. To clarify the underlying mechanisms of these side-effects we have here recorded neurophysiological activity in distributed brain networks involved in decision-making and memory functions in adult rats exposed to cranial irradiation on postnatal day 21. Multi-structure local field potential (LFP) recordings revealed decreased power in irradiated animals in the 4-9 Hz frequency band. Additionally, a distinct slowing of the oscillatory activity was observed preceding erroneous choice in a decision-making task. Moreover, irradiated rats showed reduced dynamics and a fragmented pattern of inter-structural coherence across different phases of the task. Our results suggest that the cognitive deficits and reduced processing speed following irradiation of the juvenile brain arise as a consequence of changes in long-range functional connectivity, including thalamocortical circuits, causing abnormally slow and spatially fractionated patterns of coordinating LFP activity.

neuroscience↗

bioRxiv2024

Hypoxia-induced Complement Component 3 Promotes Aggressive Tumor Growth in the Glioblastoma Microenvironment

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single cell, and spatially resolved transcriptomic data from human GBM patients. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level-dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. Presence of C3 increased proliferation of GBM cells under hypoxic conditions, as well as clonal survival of GBM cells following radiation. Targeting C3aR using the antagonist SB290157 decreased GBM cell self-renewal in vitro, and prolonged survival of glioma bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM, and support a role of hypoxia-induced C3a-C3aR signaling as a contributor to glioma aggressiveness.

cancer biology↗