Biology subjects

Jensen, R.

Publications and source records attributed to Jensen, R..

11 recordsLinked to original sources

bioRxiv2026

Comprehensive analysis of TEAD inhibition in meningioma identifies MEK and mTOR inhibition as effective combination therapies against resistant lines.

Meningiomas are the most common primary central nervous system tumors in adults, posing a significant burden to society. Although a large percentage of lower-grade meningiomas are curable by surgery or radiation alone, high-grade and a subset of low-grade meningiomas demonstrate recurrences and complications from treatment. Systemic therapies for meningioma remain ineffective, and no targeted treatments are approved. Despite the central role of YAP1/TAZ-TEAD signaling in NF2-deficient/mutant tumors, no studies have systematically examined TEAD inhibition across molecularly defined meningioma subtypes or investigated mechanisms of resistance in this disease. We have recently shown that YAP1/TAZ signaling is an oncogenic driver of meningioma. Here, using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency. Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit. Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.

cancer biology↗

bioRxiv2026

Single-cell analysis of sterol-induced Ca2+ signaling in human astrocytes by dynamic mode decomposition

Ca2+ signaling in astrocytes is a central mechanism of intercellular communication in the brain and plays a key role in regulating neuronal excitability, synaptic plasticity, and energy metabolism. Disruption of astrocytic Ca2+ dynamics is a characteristic of neurodegenerative diseases, as are deviations in cholesterol trafficking and metabolism, which are essential for maintaining membrane structure and function. Although recent studies have begun to explore links between Ca2+ signaling and sterol homeostasis in astrocytes, unbiased analytical workflows and mechanistic insight into how cholesterol and related sterols regulate astrocytic Ca2+ dynamics remain limited. Here, we apply dynamic mode decomposition to dissect and classify Ca2+ signals obtained from time-lapse imaging of human astrocytes. Using both synthetic and experimental datasets, we show that delay-embedded dynamic mode decomposition combined with clustering separates heterogeneous Ca2+ activity into distinct dynamical states. This analysis reveals that increasing cholesterol levels shift astrocytes toward more active oscillatory states, whereas acute cholesterol depletion suppresses Ca2+ activity. In addition, pretreatment with the oxysterols 24-, 25-, and 27-hydroxycholesterol impaired cholesterolinduced Ca2+ oscillations. Together, this work presents a general computational framework for decomposing and analyzing complex spatiotemporal Ca2+ signals, with broad applicability to quantitative imaging in cell biology.

biophysics↗

bioRxiv2026

A single BRCA2 BRC repeat supports viability while multiple repeats ensure resilience under stress

BRC repeats are integral to BRCA2 function and mediate RAD51 loading during homologous recombination (HR). Their number varies across species, but mammals, including mice and humans, harbor eight repeats. Prior studies have suggested functional redundancy among these repeats, but the biological significance of maintaining multiple repeats remains unresolved. Here, we demonstrate that the presence of a single BRC repeat, either BRC2 or BRC4, is sufficient for mouse embryonic stem cell (mESC) viability, RAD51 loading, PARP inhibitor resistance and protection of stalled replication forks. Consistent with these findings, we show that knock-in mice with a single BRC repeat 2 or 4 are viable and exhibit normal growth and fertility. In contrast, embryonic fibroblasts from these mice display genomic instability and impaired RAD51 recruitment. Notably, this defect is rescued under low oxygen culture conditions, which mimics physoxic levels, whereas exposure to oxidative stress impairs RAD51 recruitment in mESCs harboring a single BRC repeat. Together, our findings indicate that while a single BRC repeat is sufficient under physiological conditions, the evolutionary retention of multiple BRC repeats likely ensures robust genome stability under extreme oxidative stress.

genetics↗

bioRxiv2025

Modeling MEK-inhibitor Associated Retinopathy in vitro using human induced-1 pluripotent stem cell-derived retinal pigment epithelial cells

Pharmacologic inhibitors of MEK are important anti-cancer drugs but can result in MEK inhibitor-Associated Retinopathy (MEKAR) in which vision is lost due to serous retinal detachments that form via an unknown mechanism. We hypothesized that the cause of this side effect is drug-induced dysfunction of retinal pigment epithelial (RPE) cells. To test this hypothesis, we used human induced pluripotent stem cell-derived RPE cells. We treated mature, hiPSC-derived RPE cells with selumetinib and measured impacts on RPE-specific function, structure, and gene expression. Selumetinib increases the ability of hiPSC-derived RPE to internalize bovine rod outer segments (1.9 vs 3.0, p=0.0024). It also decreases expression of aquaporin 1 during the first 10 days of treatment (2.7 vs 1.1, p=0.0015). It has no effect on the ability of hiPSC-derived RPE to maintain membrane integrity. Selumetinib alters gene expression of hiPSC-derived RPE, with significant changes in genes involved in transport of ions and small molecules regulating cell volume and lysosomal acidification. Selumetinib may lead to subretinal fluid accumulation by both increasing secretions into this space and decreasing outflow.

molecular biology↗

bioRxiv2024

Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRT). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved anti-malarial drug, Atovaquone (AVO). We then establish the utility of Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT), a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment which results in complete elimination of tumors in all tested mice when combined with 10 Gy radiotherapy, a dose several times lower than the current clinic standard. Finally, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual clinical patient population. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

bioengineering↗

bioRxiv2023

MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch

The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch.

genomics↗

bioRxiv2021

Translational modeling of non-traumatic raised intracranial pressure in rodents; the impact of diet-induced obesity on cephalic hypersensitivity and retinal degeneration

Elevated intracranial pressure (ICP) is observed in many brain disorders. Obesity has been linked to ICP pathogenesis in disorders such as idiopathic intracranial pressure (IIH). We investigated the effect of diet induced obesity (DIO) on ICP and clinically relevant sequelae. Rats were fed either a control or high fat diet. Following weight gain long term ICP, headache behavior, body composition and retinal outcome were examined. Post-hoc analysis of retinal histology and molecular analysis of choroid plexus and trigeminal ganglion (TG) were performed. DIO rats demonstrated raised ICP by 55% which correlated with the abdominal fat percentage and increased non-respiratory slow waves, suggestive of altered cerebral compliance. Concurrently, DIO rats demonstrated a specific cephalic cutaneous allodynia which negatively correlated with the abdominal fat percentage. This sensitivity was associated with increased expression of headache markers in TG. Additionally, DIO rats had an in vivo increased retinal nerve fiber layer thickness associated with raised ICP with a subsequent post-hoc demonstration of neuroretinal degeneration. This study demonstrates for the first time that DIO leads to raised ICP and subsequent clinically relevant symptom development. This novel model of non-traumatic raised ICP could expand the knowledge regarding disorders with elevated ICP such as IIH.

neuroscience↗

bioRxiv2020

Varia: Prediction, analysis and visualisation of variable genes

Assessing the diversity or expression of variable gene families in pathogens can inform about immune escape mechanisms or host interaction phenotypes of clinical relevance. However, obtaining the sequences and quantifying their expression is a challenge. Here, we present a tool, which based on unique sequence tag similarity between members of a gene family, predicts the domains encoded by the queried gene. As an example, we are using the var gene family, encoding the major virulence proteins (PfEMP1) of the human malaria parasite, Plasmodium falciparum. We developed Varia, which predicts the likely var gene sequence and encoded protein domain composition of a gene from short sequence tags. We provide a new extended annotated var genome database, in which Varia identifies genes with identical tag sequences and compares these to return the most probable domain composition of the query gene. Varias ability to predict correct PfEMP1 domain compositions from short var sequence tags was tested in two complementary pipelines to (a) return the putative gene sequences and domain compositions of the query gene from any partial sequence provided, thereby enabling detailed assessment of specific genes putative function and experimental validation of these (b) to accommodate rapid profiling of var gene expression in complex patient samples, by compiling the overall domain prevalence among var transcripts predicted identified and quantified by next generation sequencing of so-called var DBL-sequence tags. Availability and implementationVaria is available on GitHub (https://github.com/GCJMacken-zie/Varia) under the MIT license. Contactthomasl@sund.ku.dk, thomasdan.otto@glasgow.ac.uk

bioinformatics↗

bioRxiv2020

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor -like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.

physiology↗

bioRxiv2019

Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches

When interpreting sequencing data from multiple spatial or longitudinal biopsies, detecting sample mix-ups is essential yet more difficult than in studies of germline variation. In most genomic studies of tumors, genetic variation is frequently detected through pairwise comparisons of the tumor and a matched normal tissue from the sample donor, and in many cases, only somatic variants are reported. The disjoint genotype information that results hinders the use of existing tools that detect sample swaps solely based on genotypes of germline variants. To address this problem, we have developed somalier, which can operate directly on the alignments, so as not to require jointly-called germline variants. Instead, somalier extracts a small sketch of informative genetic variation for each sample. Sketches from hundreds of biopsies and normal tissues can then be compared in under a second. This speed also makes it useful for checking relatedness in large cohorts of germline samples. Somalier produces both text output and an interactive visual report that facilitates the detection and correction of sample swaps using multiple relatedness metrics. We introduce the tool and demonstrate its utility on a cohort of five glioma samples each with a normal, tumor, and cell-free DNA sample. Applying somalier to high-coverage sequence data from the 1000 Genomes Project also identifies several related samples. Somalier can be applied to diverse sequencing data types and genome builds, and is freely available for academic use at github.com/brentp/somalier.

bioinformatics↗

bioRxiv2019

Establishing reference samples for detection of somatic mutations and germline variants with NGS technologies

We characterized two reference samples for NGS technologies: a human triple-negative breast cancer cell line and a matched normal cell line. Leveraging several whole-genome sequencing (WGS) platforms, multiple sequencing replicates, and orthogonal mutation detection bioinformatics pipelines, we minimized the potential biases from sequencing technologies, assays, and informatics. Thus, our \"truth sets\" were defined using evidence from 21 repeats of WGS runs with coverages ranging from 50X to 100X (a total of 140 billion reads). These \"truth sets\" present many relevant variants/mutations including 193 COSMIC mutations and 9,016 germline variants from the ClinVar database, nonsense mutations in BRCA1/2 and missense mutations in TP53 and FGFR1. Independent validation in three orthogonal experiments demonstrated a successful stress test of the truth set. We expect these reference materials and \"truth sets\" to facilitate assay development, qualification, validation, and proficiency testing. In addition, our methods can be extended to establish new fully characterized reference samples for the community.

bioinformatics↗