Biology subjects

Persson, O.

Publications and source records attributed to Persson, O..

4 recordsLinked to original sources

bioRxiv2025

Organotypic Timelapse recording with Transcriptomic Readout (OTTR) links cell behaviour to cell identity in human tissues

Linking dynamic cellular behaviour to molecular states in intact human tissue remains challenging because during live imaging only limited molecular information can be captured while high-dimensional molecular measurements are destructive. Here we describe Organotypic Timelapse recording with Transcriptomic Readout (OTTR), which integrates week-long live imaging of sparsely labelled organotypic slice cultures with highly multiplexed in situ spatial transcriptomics. We applied OTTR to primary human glioblastoma and fetal cortical tissues. Using sparse labelling, we tracked the migration, proliferation, and lineage of tens of thousands of individual cells per sample. Following live imaging, precision resectioning and alignment allowed us to perform spatial transcriptomics on the very same tissue, thereby preserving the link between dynamic cell behaviours and transcriptomic states. We used OTTR to quantify cell-type specific migration patterns, lineage trees and the behaviour of cells near vasculature. OTTR provides a powerful, broadly applicable method for investigating the complex interplay between cell behaviour and molecular state in human tissues.

molecular biology↗

bioRxiv2025

Cell atlas of the developing human meninges reveals a dura origin of meningioma

The vertebrate central nervous system is enveloped by the meninges, consisting of the pia, arachnoid, and dura layers. The arachnoid is hypothesised to give rise to the most common primary intracranial tumours, meningiomas. However, molecular evidence supporting this hypothesis is lacking. There are no effective medical therapies to treat meningiomas that are resistant to local interventions, encumbered by our limited understanding of their cellular origin. To address this limitation in our understanding of meningioma biology, we generated a comprehensive reference single cell and spatial transcriptomic atlas of human fetal meninges at post-conceptional weeks 5-13. We found that the meningeal layers develop concurrently, and identified an inner CDH1-positive dura cell layer expressing tight junction genes consistent with barrier function. We show that transcriptionally, meningioma cells resemble dura-lineage cells, and that common meningioma driver genes were expressed preferentially in the dura lineage. Our findings suggest that meningiomas originate from dura lineage cells. HIGHLIGHTSO_LIscRNA-seq and spatial transcriptomics reveals architecture of human fetal meninges development C_LIO_LIMeningeal layers are formed concurrently, by a gradual refinement of cell states C_LIO_LIA CDH1+ inner dura sublayer expresses tight junction genes like the arachnoid barrier C_LIO_LIMeningioma tumours likely originate from inner dura lineage cells, not arachnoid C_LI

developmental biology↗

bioRxiv2024

SOX21 suppresses GBM growth by repressing AP-1 regulated target genes

BackgroundTreatment-resistant glioblastoma stem cells (GSCs) drive glioblastoma (GBM) growth and recurrence. Thus, targeting the molecular machinery that sustains GSCs in an undifferentiated and self-renewing state is a promising therapeutic strategy. The transcription factor SOX21 effectively suppresses the tumorigenic capacity of GSCs. However, the mechanism by which SOX21 impedes GSC features is unknown. MethodsPatient-derived GSCs were engineered with a transgenic TetOn system to enable inducible expression of SOX21 or appropriate controls. The capacity of SOX21 to incapacitate GSCs was assessed using in vitro cell culture models and orthotopic mouse models. Cellular and genome-wide techniques, including RNA-seq, ChIP-seq, and ATAC-seq, were employed to examine the mechanisms by which SOX21 regulates GSCs. ResultsWe show that SOX21 expression in primary GSCs induces an anti-tumorigenic transcriptional program, aligning with clinical data showing a positive correlation between SOX21 levels and improved GBM patient survival. Induced SOX21 expression in GSCs within pre-established GBM reduces their capacity to sustain tumor growth and significantly extends the survival of the transplanted mice. Mechanistically, SOX21 functions as a tumor suppressor by binding a large set of AP-1-targeted chromatin regions, leading to epigenetic repression of AP-1-activated genes that support GSC survival and proliferation. Consistently, the anti-tumorigenic activities of SOX21 are replicated by AP-1 inhibitors, while overexpression of the AP-1 family member, c-JUN, counteracts these effects. ConclusionOur findings identify SOX21 as a key regulator that prevents GSC malignancy by targeting and repressing an AP-1-driven, tumor-promoting gene expression program. These results highlight SOX21-regulated pathways as promising therapeutic targets for GBM. Key PointsO_LIInduced SOX21 expression suppresses GSCs and inhibits the growth of established GBM C_LIO_LISOX21 acts as a tumor suppressor in GSCs by directly repressing AP-1-driven genes C_LIO_LIPharmacological inhibition of AP-1 mimics SOX21 activity in GSCs C_LI Importance of the StudyGBM is the most common and aggressive malignant brain tumor in adults. Recurrence following treatment often stems from the failure of therapeutic interventions to effectively target GSCs, which serve as the primary reservoir for tumor regrowth. The resilience of GSCs to treatment is partly due to the inactivation of intrinsic tumor suppressor programs that would otherwise direct GSCs to cellular senescence and death. This study demonstrates that increased expression levels of the tumor suppressor SOX21 in pre-established GBM disrupt tumor progression by disabling self-renewing GSCs. We show that SOX21 exerts its tumor-suppressive function by targeting and repressing an AP-1-driven gene network, which is a key regulator of GSC maintenance and proliferation. By uncovering the molecular mechanisms through which SOX21 controls GSC biology, our findings provide valuable insights for basic cancer research and may inform the development of novel therapeutic strategies for GBM.

cancer biology↗

bioRxiv2023

Glioblastoma is spatially organized by neurodevelopmental programs and a glial-like wound healing response

Glioblastoma is the deadliest brain cancer, characterized by large cellular diversity whose complexity and organizing principles are only starting to be uncovered. Both neurodevelopment-like and mesenchymal-like cell states have been described in glioblastoma1-8, with the latter being strongly implicated in malignancy and disease progression8-11. However, the nature of these mesenchymal-like cell states remains unresolved. Here, we performed deep single-cell RNA sequencing of rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex. We discovered that previously defined mesenchymal-like tumor cell states instead represented a wound response that was shared across both malignant and non-malignant cell types and was spatially confined to the tumor bulk. Using glioblastoma organoids, we showed that the wound response transcriptional state could be reversibly induced in vitro by hypoxia and human plasma. We used multiplex single-molecule spatial transcriptomics12 on a large patient cohort to show that the activation of wound response states was associated with hypoxia, and organized by distance to perivascular niches. Our findings help reconceptualize the cellular landscape of glioblastoma, wherein a reactive wound-response tissue state shared by all cells in the tumor bulk is superimposed on a fundamentally neurodevelopmental and glial tumor.

cancer biology↗