Biology subjects

Neumann, J. E.

Publications and source records attributed to Neumann, J. E..

5 recordsLinked to original sources

bioRxiv2025

Expression of LTR and LINE1 transposable elements defines atypical teratoid/rhabdoid tumor subtypes

Atypical teratoid rhabdoid tumors (ATRTs) are aggressive central nervous system tumors mainly affecting young children. Extensive molecular characterization based on gene expression and DNA methylation patterns has solidly established three major ATRT subtypes (MYC, SHH and TYR), which show distinct clinical features, setting the basis for more effective, targeted treatment regimens. Transcriptional activity of transposable elements (TEs), like LINE1s and LTRs, is tightly linked with human cancers as a direct consequence of lifting epigenetic repression over TEs. The sole recurrent biallelic loss-of-function mutation in SMARCB1 in ATRTs, a core component of the SWI/SNF chromatin remodeling complex, raises the question of how TE transcription contributes to ATRT development. Here, we comprehensively investigate the transcriptional profiles of 1.9M LINE1 and LTR elements across ATRT subtypes in primary human samples. We find TE transcription profiles are unique, allowing sample stratification into ATRT subtypes. The TE activity signature in ATRT-MYC subtype is unique, setting these tumors apart from SHH and TYR ATRTs. More specifically, ATRT-MYC shows broadly reduced transcript levels of LINE1 and ERVL-MaLR subfamilies. ATRT-MYC is also unique in having significantly less LTR and LINE1 loci with bidirectional promoter activity. Furthermore, we identify 849 differentially transcribed TEs in primary samples, which are predictive towards established ATRT-SHH and-MYC cell line models. In summary, including TE transcription profiles into the molecular characterization of ATRTs might reveal new tumor vulnerabilities leading to novel therapeutic interventions, such as immunotherapy.

cancer biology↗

bioRxiv2025

OmixLitMiner 2: Guided Literature Mining Tools for Automated Categorization of Marker Candidates in Omics Studies

Omics analyses are crucial for understanding molecular mechanisms in biological research. The vast quantity of detected biomolecules presents a significant challenge in identifying potential biomarkers. Traditional methods rely heavily on labor-intensive literature mining to extract meaningful insights from long lists of regulated candidates. To address this, we developed OmixLitMiner 2 to improve the efficiency of omics data interpretation, increase the speed for the validation of results and accelerate further evaluation based on the selection of marker candidates for subsequent experiments. The updated tool utilizes UniProt for synonym and protein name retrieval and employs the PubMed database as well as PubTator 3.0 for mining abstracts and full texts of available biomedical literature. It allows for advanced keyword-based searches and provides classification of proteins or genes with respect to their awareness level in relationship to scientific questions. OmixLitMiner 2 offers improved functionality over the previous version and comes with a user-friendly Google Colab interface. In comparison to the previous version OmixLitMiner 2 improves the retrieval and classification of relevant publications. The tool significantly reduces the time required for manual searches, as demonstrated in a case study involving proteomic data from spatially resolved mouse brain cortex layers. Statement of SignificanceWe developed OmixLitMiner 2 to determine, for a given set of marker candidates, the extent to which they have been described in the literature. The tool is easy-to-use and can quickly generate a categorized list of references obtained by automated literature searches for protein and gene names and involving keywords related to a specific scientific question. The categorization provides a ranking of how well-studied the genes or proteins: Candidates of category 1 are well-known regarding the scientific question; Candidates of category 2 have been mentioned in a publication associated with the specific scientific question; Candidates of category 3 have never been described to be associated with the specific scientific question; Candidates of category 4 are not yet known proteins and are not associated with a gene name. This classification can aid in the decision, which protein or gene candidates to choose for follow-up experiments.

bioinformatics↗

bioRxiv2024

Co-activation of LIN28A and CTNNB1 disturbs cortical neuronal migration and pia mater integrity

Developmental signalling pathways act in stage and tissue dependent relation and mis-activation can drive tumour formation. The RNA-binding protein LIN28A maintains stemness and is overexpressed in embryonal brain tumours. Activating mutations of CTNNB1 - the WNT pathway effector - have been reported in respective brain tumours. The aim of this study was to investigate the interplay of these oncogenic proteins during embryonal brain development. The combination of both oncogenic factors did not lead to brain tumour formation but resulted in disturbed lamination and impaired cell migration in the cerebral cortex. Spatially resolved proteome analysis revealed imbalances of the extracellular matrix protein LAMB1 and its receptors RPSA and ITGB1 accompanied by a porous pial border and overmigration of neural cells. Cajal-Retzius cells were misplaced in deeper cortex regions without affecting general REELIN levels and additional reduced levels of -DYSTROGLYCAN. Taken together, the interplay of LIN28A and CTNNB1 resulted in a cortical migration disorder showing histomorphological and molecular similarities to human Cobblestone lissencephaly (type 2), highlighting novel implications of the oncogene LIN28A in extracellular matrix integrity.

neuroscience↗

bioRxiv2023

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases

Proteolytic cell surface release ( shedding) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated for the human body thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimers disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregates of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.

neuroscience↗

bioRxiv2023

Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level

Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically very heterogenous. To unravel phenotypically relevant MB subtypes, we compiled a harmonized proteome dataset of 167 MBs and integrated findings with DNA methylation and N-glycome data. Six proteome MB subtypes emerged, that could be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pGroup3-Myc), and synapses/immunological processes (pSHHs, pGroup3 and pGroup4). Multiomic analysis revealed different conservation levels of proteome features across MB subtypes at the DNA-methylation level. Aggressive pGroup3-Myc MBs and favorable pWNT MBs were most similar in cluster hierarchies concerning overall proteome patterns but showed different protein abundances of the vincristine resistance associated multiprotein complex TriC/CCT and of N-glycan turnover associated factors. The N-glycome reflected proteome subtypes and complex-bisecting N-glycans characterized pGroup3-Myc tumors. Our results shed light on new targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures. SignificanceWhereas the application of omics technologies has significantly improved MB tumor classification and treatment stratification, it is still of debate, which features predict best clinical outcome. Moreover, treatment options - especially for high-risk groups - are still unsatisfactory. In contrast to nucleic acids, the proteome and their N-glycans may reflect the phenotype of a tumor in a more direct way and thus hold the potential to discover clinically relevant phenotypes and potentially targetable pathways. We show that these analyses are feasible on formalin fixed and paraffine embedded tissue. Compiling a comprehensive MB dataset, we detected new biomarkers and characteristics for high- and low-risk MB subtypes that were not reflected by other omic data modalities before. Specifically, we identified subtype specific abundance differences in proteins of the vincristine resistance associated multiprotein complex TriC/CCT and in proteins involved in N-glycan turnover. Changes in the N-glycans are considered as potential hallmarks of cancer and we show that N-glycan profiles can distinguish MB subtypes. These tumor-specific N-glycan structures hold a strong potential as new biomarkers, as well as immunotherapy targets. Highlights- Integration of in-house proteome data on formalin fixated paraffine embedded medulloblastoma (MB) and publicly available datasets enables large scale proteome analysis of MB - Six proteome MB subtypes can be assigned to two main molecular programs: replication/ translation versus synapse/immune system - Identification and validation of IHC compatible protein-biomarkers for high and low risk MB subtypes, such as TNC and PALMD. - Subtype specific correlation of the DNA methylome and the proteome reveals different conserved molecular characteristics across MB subtypes. - pGroup3-Myc subtype MBs are associated with high-risk features including high abundances of vincristine resistance associated TriC/CCT member proteins - Proteome MB subtypes show differential N-glycosylation patterns, revealing complex-bisecting glycans as potentially immunotargetable hallmarks of the high risk pGroup3-Myc subtype.

cancer biology↗