Biology subjects

Neumann, E.

Publications and source records attributed to Neumann, E..

7 recordsLinked to original sources

bioRxiv2026

Metabolic niches: MALDI imaging reveals lipidomic heterogeneity in the human heart

The human heart is characterized by aberrant lipid accumulation and remodeling during periods of stress and disease, yet spatially resolved lipidomic profiling of the human heart remains unreported. Here, we employ matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to map lipid distributions across five anatomical regions of healthy human donor hearts (left and right atrium, left and right ventricle, and interventricular septum). Cryosections of donor hearts from healthy subjects were thaw-mounted onto indium tin oxide slides, coated with 2,5-dihydroxyacetophenone, and analyzed on a Bruker timsTOF fleX mass spectrometer in positive and negative ionization modes (50-1850 m/z; 20 m raster). Serial sections were stained with hematoxylin and eosin to enable histological co-registration with lipid distributions. We identified 150 unique lipid species with acyl-chain resolution across four glycerophospholipid classes -- phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and phosphatidylserine (PS) -- with abundances and spatial distributions differing significantly between regions. H&E co-registration further resolved epicardial and myocardial compartments, enabling tissue-specific lipid mapping. These findings establish the first spatially resolved lipidomic atlas of the human heart and provide a framework for identifying region-specific lipid biomarkers of cardiovascular disease.

Molecular Biology↗

bioRxiv2025

Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

cancer biology↗

bioRxiv2025

Unraveling the molecular mechanism underlying the anticancer activity of CISD2/NAF-144-67

We recently reported on the development of a unique cancer-targeting peptide called NAF-144-67 (derived from CISD2/NAF-1). NAF-144-67 selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-144-67 also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-144-67 through cancer cell PMs was studied, and its cancer killing effects validated in vitro and in vivo, little is known about how NAF-144-67 exerts its biological activity once it enters cancer cells. Here, we report that NAF-144-67 targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-144-67 (at two different orientations) have higher anticancer activity compared to monomeric NAF-144-67. Our findings shed new light on the biological activity of NAF-144-67 and bring it closer to becoming a potential new anticancer drug.

cancer biology↗

bioRxiv2024

Targeting primary and metastatic ovarian cancer with a peptide derived from the human NAF-1/CISD2 protein

Ovarian cancer is the most fatal cancer of female reproductive organs. Ovarian cancer is typically diagnosed at a late stage, after metastasis occurred, leading to a 5-years relative survival rate of only [~]5%. Here, we demonstrate the anti-ovarian cancer properties of a peptide derived from the human protein CISD2/NAF-1 (3D-NAF-144-67-6K). This peptide selectively permeates the plasma membrane of ovarian cancer SKOV-3 cells without affecting healthy cells. 3D-NAF-144-67-6K targets and destroys the cancer cells mitochondria which leads to cancer cell death. In vivo studies of mice carrying xenograft tumours of SKOV-3 showed that the peptide significantly decreased the overall size and growth rate of both primary and metastatic ovarian cancer tumours. We further show that 3D-NAF-144-67-6K has a broad-spectrum anticancer activity targeting leukaemia, brain, and pancreas cancer cells. Our study suggests that 3D-NAF-144-67-6K could be used, alone or in drug combinations, to treat ovarian cancer and improve patient survival.

cancer biology↗

bioRxiv2020

Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

evolutionary biology↗

bioRxiv2020

Cell-intrinsic Innate Immune Responses against Chikungunya Virus in a Human Ex Vivo Synovial Fibroblast Model

In recent years, (re-)emerging arboviruses including Chikungunya virus (CHIKV) and Mayaro virus (MAYV) have caused growing concern due to expansion of insect vector ranges. No protective vaccine or specific antiviral strategies are currently available. Long-term morbidity after CHIKV infection includes debilitating chronic joint pain, which has associated health and economic impact. Here, we analyzed the early cell-intrinsic response to CHIKV and MAYV infection in primary human synovial fibroblasts. This interferon-competent cell type represents a potential source of polyarthralgia induced by CHIKV infection. Synovial fibroblasts from healthy and osteoarthritic donors were similarly permissive to CHIKV and MAYV infection ex vivo. Using RNA-seq, we defined a CHIKV infection-induced transcriptional profile with several hundred interferon-stimulated and arthralgia-mediating genes upregulated. Type I interferon was both secreted by infected fibroblasts and protective when administered exogenously. IL-6 secretion, which mediates chronic synovitis, however, was not boosted by infection. Single-cell RNA-seq and flow cytometric analyses uncovered an inverse correlation of activation of innate immunity and productive infection at the level of individual cells. In summary, primary human synovial fibroblasts serve as bona-fide ex vivo primary cell model of CHIKV infection and provide a valuable platform for studies of joint tissue-associated aspects of CHIKV immunopathogenesis.

microbiology↗

bioRxiv2019

Correlating surface plasmon resonance microscopy of living and fixated cells with electron microscopy allows for investigation of potential preparation artifacts

AO_SCPLOWBSTRACTC_SCPLOWThe investigation of the cell-substrate interface is of great importance for a broad spectrum of areas such as biomedical engineering, brain-chip interfacing and fundamental research. Due to its unique resolution and the prevalence of instruments, electron microscopy (EM) is used as one of the standard techniques for the analysis of the cell-substrate interface. However, possible artifacts that might be introduced by the required sample preparation have been the subject of speculation for decades. Due to recent advances in Surface plasmon resonance microscopy (SPRM), the technique now offers a label-free alternative for the interface characterization with nanometer resolution in axial direction. In contrast to EM, SPRM studies do not require fixation and can therefore be performed on living cells. Here, we present a workflow that allows us to quantify the impact of chemical fixation on the cell-substrate interface. These measurements confirmed that chemical fixation preserved the average cell-substrate distances in the majority of studied cells. Furthermore, we were able to correlate the SPRM measurements with EM images of the cell-substrate interface of the exact same cells allowing us to identify regions with good agreement between the two methods and reveal artifacts introduced during further sample preparation.

biophysics↗