Biology subjects

Scholl, C.

Publications and source records attributed to Scholl, C..

13 recordsLinked to original sources

bioRxiv2026

Alternative lengthening of telomeres stratifies complex karyotype sarcomas into distinct genomic and transcriptomic states

Complex karyotype sarcomas (CKS) are heterogeneous mesenchymal malignancies that typically lack recurrent actionable oncogenic drivers and remain therapeutically challenging. Loss of ATRX is a recurrent feature of CKS and defines a particularly high-risk subgroup. ATRX loss is also associated with activation of the alternative lengthening of telomeres (ALT) pathway, and ALT-positive sarcomas have been linked to poor clinical outcomes. However, the molecular underpinnings underlying ALT-status-dependent differences in CKS, as well as the therapeutic vulnerabilities associated with ALT, remain poorly defined. By integrating C-circle-based ALT detection across 776 sarcoma samples with multi-modal sequencing of five CKS subtypes, we find that ALT activity is associated with enriched hallmarks of genomic instability. ALT-positive transcriptomes are dominated by a coordinated DNA damage response and mitotic program, in contrast to oncogenic signaling pathways that drive TERT activation in ALT-negative tumors. Long-read sequencing reveals telomere repeat clusters and telomere-mediated healing at structural breakpoints in ALT-positive tumors. These events also occur on extrachromosomal DNA (ecDNA), linking ALT activity to ecDNA biology. Together, our findings position ALT status as an important stratifying feature of CKS and identify ALT-associated transcriptional programs as potential therapeutic targets.

cancer biology↗

bioRxiv2026

Systematic functional drug testing in patient-derived models reveals ex vivo sensitivities associated with clinical outcome in rare solid tumors

Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers. Statement of SignificanceThis study presents a biopsy-compatible drug sensitivity testing platform for phenotype-based therapy stratification in rare cancers. It identifies actionable ex vivo drug responses and shows associations with clinical outcome in patients treated with screened therapies. These findings support functional testing as a complementary additional layer of stratification for therapeutic prioritization.

cancer biology↗

bioRxiv2025

Tracking Sleep-Linked Brain Fluid Dynamics Using Modified fNIRS: A Novel Noninvasive Window into Glymphatic Function

BackgroundThe glymphatic system, a brain-wide perivascular and interstitial waste and signal transport pathway for cerebrospinal fluid (CSF) to exchange with interstitial fluid (ISF), has pronounced activity during non-rapid eye movement (NREM) sleep and has been implicated in the pathophysiology of traumatic brain injury, Alzheimers disease, and mood disorders. However, direct measurement in humans is limited because current imaging methods rely on intrathecal contrast-enhanced magnetic resonance imaging (MRI), which is unsuitable for routine or naturalistic sleep studies. The absence of real-time, noninvasive monitoring methods that allow for natural sleep poses a major barrier to advancing glymphatic research in clinical settings. MethodsTo address this barrier, we developed a non-invasive functional near-infrared spectroscopy (fNIRS) forehead array in a wearable headband using non-standard wavelengths to allow for better sensitivity for water measurement. We monitored cortical blood and water dynamics during overnight sleep, quantifying oscillatory patterns of oxyhemoglobin (HbO) and water across sleep stages within the outer layers of the frontal cortex, subarachnoid space, and scalp. A component of the extracted water metrics is hypothesized to serve as a proxy for glymphatic transport without the need for contrast agents or surgical intervention. ResultsOur results demonstrate water concentrations were highest in SWS (d = 1.93, p=0.0002), while HbO concentrations also showed a modest elevation (d = 1.06, ns). Additionally, low-frequency oscillations (LFOs) of both water and HbO signals exhibited distinct dynamics of suprathreshold envelope peak (SEP) frequencies during NREM stages (N2 and N3) as compared to REM and wake, with effect size (d= 1.31, p = 0.003) for water. Interestingly, these water-derived metrics correlate with EEG slow-wave activity, linking fluid-sensitive oscillations to established electrophysiological markers of sleep depth. These findings indicate that water-sensitive oscillatory processes are selectively amplified during deep sleep and scale with EEG-defined sleep depth, consistent with a role for glymphatic-related fluid transport in human sleep. ConclusionWe report novel cortical water shift parameters that are robustly sensitive to sleep stage transitions via a wearable, non-invasive, scalable headband, consistent with predicted glymphatic activity. Future work will cross-validate this method with MRI and other techniques. DisclaimerThe views, information or content, and conclusions presented do not represent the official position or policy of, nor should any official endorsement be inferred on the part of, the Uniformed Services University, the Department of War, the U.S. Government, or Walter Reed National Military Medical Center.

neuroscience↗

bioRxiv2024

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXTs downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.

cancer biology↗

bioRxiv2024

Exploiting WEE1 kinase activity as FUS::DDIT3-dependent therapeutic vulnerability in myxoid liposarcoma

The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. Since FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3-dependent therapeutic vulnerability in MLS. Here we demonstrate that enhanced WEE1 pathway activity represents a hallmark of FUS::DDIT3-expressing cell lines as well as MLS tissue specimens and that WEE1 is required for MLS cellular survival in vitro and in vivo. Pharmacologic inhibition of WEE1 activity results in DNA damage accumulation and cell cycle progression forcing cells to undergo apoptotic cell death. In addition, our results uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic survival mechanism to tolerate high proliferation and resulting replication stress in MLS. Fusion protein-driven G1/S cell cycle checkpoint deregulation via overactive Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1 inhibitor sensitivity in MLS. These findings identify WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.

cancer biology↗

bioRxiv2024

Somatic gene delivery for flexible in vivo modeling of high-risk sarcoma

A particular challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma entities and the corresponding lack of suitable model systems to recapitulate and study these diseases. To overcome this predicament, we developed a novel genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by electroporation (EPO) of the thigh muscle wildtype mice. This optimized sarcoma EPO-GEMM (EPO-based genetically engineered mouse model) platform allowed the generation of ten biologically distinct sarcoma entities, including Synovial Sarcoma (SS), fusion-positive and fusion-negative Rhabdomyosarcoma (RMS), Alveolar Soft Part Sarcoma (ASPS), Undifferentiated Pleomorphic Sarcoma (UPS) and Infantile Fibrosarcoma (IFS). Comprehensive molecular profiling and cross-species analyses confirmed faithful recapitulation of the human disease, including the expression of relevant immunotherapy targets. Syngeneic allografting enabled reliable preservation and scalability of Sarcoma-EPO-GEMMs for treatment trials, such as B7-H3-directed CAR-T cell therapy in an immunocompetent background.

cancer biology↗

bioRxiv2023

Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions

Linking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception. SIGNIFICANCEMost rare cancers are poorly understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. This study illustrates the potential of linking precision oncology programs with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers that could improve the clinical management of such diseases.

cancer biology↗

bioRxiv2023

Cell division tracing combined with single-cell transcriptomics reveals new cell types and differentiation paths in the regenerating mouse lung

Understanding the molecular and cellular processes involved in lung epithelial regeneration may fuel the development of new therapeutic approaches for lung diseases. We combined new mouse models that allow diphtheria toxin (DTA)-mediated depletion of specific epithelial cell types and GFP-labeling of dividing cells with single-cell transcriptomics to characterize the regeneration of the distal lung. We uncovered new cell types, some of which likely represent epithelial precursors, propose goblet cells as progenitor cells, and provide evidence that adventitial fibroblasts act as supporting cells in epithelial regeneration. We also found that DTA-expressing cells can persist in the lung, express specific inflammatory factors, and resemble a previously undescribed population in the lungs of COVID-19 patients. Our study provides a comprehensive single-cell atlas of the distal lung that characterizes early transcriptional and cellular responses to defined epithelial injury, encompassing proliferation, differentiation, and cell-to-cell interactions.

cell biology↗

bioRxiv2022

Shallow nanopore RNA sequencing enables transcriptome profiling for precision cancer medicine

Transcriptome profiling is a mainstay of translational cancer research and is increasingly finding its way into precision oncology. While bulk RNA sequencing (RNA-seq) is widely available, high costs and long data return time are limiting factors for clinical applications. We investigated a portable nanopore long-read sequencing device (MinION, Oxford Nanopore Technologies) for transcriptome profiling of tumors. In particular, we investigated the impact of lower coverage than that of larger sequencing devices by comparing shallow nanopore RNA-seq data with short-read RNA-seq data generated using reversible dye terminator technology (Illumina) for ten samples representing four cancer types. Coupled with ShaNTi (Shallow Nanopore Sequencing for Transcriptomics), a newly developed data processing pipeline, a turnaround time of five days was achieved. The correlation of normalized gene-level counts between nanopore and Illumina RNA-seq was high for MinION but not for very low-throughput Flongle flow cells (r = 0.89 and r = 0.24, respectively). A cost-saving approach based on multiplexing of four samples per MinION flow cell maintained a high correlation with Illumina data (r = 0.56 - 0.86). In addition, we compared the utility of nanopore and Illumina RNA-seq data for analysis tools commonly applied in translational oncology: (i) Shallow nanopore and Illumina RNA-seq were equally useful for inferring signaling pathway activities with PROGENy. (ii) Highly expressed genes encoding kinases targeted by clinically approved small-molecule inhibitors were reliably identified by shallow nanopore RNA-seq. (iii) In tumor microenvironment composition analysis, quanTIseq performed better than CIBERSORT, likely due to higher average expression of the gene set used for deconvolution. (iv) Shallow nanopore RNA-seq was successfully applied to validate known gene fusions by breakpoint analysis. These findings suggest that shallow nanopore RNA-seq enables rapid, cost-effective, and biologically meaningful transcriptome profiling of tumors and warrants further exploration in precision cancer medicine studies.

cancer biology↗

bioRxiv2021

Enhanced habit formation in Tourette syndrome : dopamine release and striatal disinhibition modulate shortcut connections in a hierarchical model of cortico-basal ganglia loops

In the Gilles de la Tourette syndrome, tics are often considered as habitual responses towards unwanted premonitory urges. Support for the relationship between tics and habits comes from devaluation protocols, which reveal that unmedicated Tourette patients show an increased tendency towards responses to devalued outcomes. We use a neuro-computational model of hierarchically organized cortico-basal ganglia-thalamo-cortical loops to shed more light on enhanced habit formation of Tourette patients. In our model, habitual behavior emerges from cortico-thalamic shortcut connections, where enhanced habit formation can be linked to faster plasticity in the shortcut or to a stronger feedback from the shortcut to the basal ganglia. Irregular activity in such shortcut connections may have different pathophysiological origins. Based on our model, we explore decreased local striatal inhibition, which may correspond to a loss of inhibitory interneurons, and increased dopaminergic modulation of striatal medium spiny neurons as causes for irregular shortcut plasticity or activation. Both lead to higher rates of response towards devalued outcomes in our model, similar to what is observed in Tourette patients. Our results support the view of tics in Tourette syndrome as maladaptive habits. We suggest to reveal more shortcuts between cortico-basal ganglia-thalamo-cortical loops in the human brain and study their potential role in the development of the Tourette syndrome.

neuroscience↗

bioRxiv2020

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N=608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

neuroscience↗

bioRxiv2020

The Information Theory of Developmental Pruning: Optimizing Global Network Architecture Using Local Synaptic Rules

During development, biological neural networks produce more synapses and neurons than needed. Many of these synapses and neurons are later removed in a process known as neural pruning. Why networks should initially be over-populated, and processes that determine which synapses and neurons are ultimately pruned, remains unclear. We study the mechanisms and significance of neural pruning in model neural network. In a deep Boltzmann machine model of sensory encoding, we find that (1) synaptic pruning is necessary to learn efficient network architectures that retain computationally-relevant connections, (2) pruning by synaptic weight alone does not optimize network size and (3) pruning based on a locally-available proxy for "sloppiness" based on Fisher Information allows the network to identify structurally important vs. unimportant connections and neurons. This locally-available measure of importance has a biological interpretation in terms of the correlations between presynaptic and postsynaptic neurons, and implies an efficient activity-driven pruning rule. Overall, we show how local activity-dependent synaptic pruning can solve the global problem of optimizing a network architecture. We relate these findings to biology as follows: (I) Synaptic over-production is necessary for activity-dependent connectivity optimization. (II) In networks that have more neurons than needed, cells compete for activity, and only the most important and selective neurons are retained. (III) Cells may also be pruned due to a loss of synapses on their axons. This occurs when the information they convey is not relevant to the target population.

neuroscience↗

bioRxiv2019

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

pharmacology and toxicology↗