Biology subjects

Schumann, U.

Publications and source records attributed to Schumann, U..

5 recordsLinked to original sources

bioRxiv2025

EGFL7 promotes immune evasion in glioma through its interaction with integrin β2

Glioblastoma is the most aggressive form of malignant brain cancer, characterized by an immunosuppressive microenvironment and immune evasion. Despite the success of immune checkpoint inhibitors in other cancers, immunotherapies such as anti-PD1 have shown limited efficacy in glioblastoma, underscoring the need to identify tumor-intrinsic mechanisms that sustain this immunosuppressive microenvironment and to develop more effective therapeutic strategies targeting them. Previously, the secreted factor epidermal growth factor-like protein 7 (EGFL7) has been shown to promote brain tumor growth by affecting the glioblastoma microenvironment (GME). However, its impact on the immune system remained enigmatic. Here, we studied the role of EGFL7 in shaping the immune landscape in glioblastoma and identified the underlying molecular mechanisms it engages to drive glioma immune evasion. Single-cell transcriptomic profiling of immune cells derived of glioblastoma revealed that EGFL7 promotes an immunosuppressive GME, characterized by enhanced T cell exhaustion and polarization of macrophages towards a protumorigenic state. Proteomic profiling of EGFL7s interactome in glioma revealed its interaction with integrin {beta}2 (ITGB2), an immune cell surface receptor involved in cell adhesion and migration. Mechanistic studies uncovered the central role of this interaction for immune evasion, which promoted T cell exhaustion and the polarization of macrophages towards a pro-tumorigenic state. Genetic perturbation of the EGFL7-ITGB2 axis attenuated immunosuppression and prolonged the survival of glioblastoma-bearing mice. Remarkably, a combinatorial regimen of anti-EGFL7 and the checkpoint inhibitor anti-PD1 improved the efficacy of this drug, which by itself did not improve glioma patient survival so far. In conclusion, our study provides unequivocal evidence that EGFL7 mediates immune evasion in glioma and has great potential to serve as an add-on drug target to improve immunotherapies not functional in glioblastoma patients so far.

cancer biology↗

bioRxiv2022

Less is more - loss of EGFL7 improves memory by upregulation of VEGF-D

Neural stem cells reside in a specialized neurogenic niche of the hippocampus termed the subgranular zone. Throughout life, they give rise to adult-born neurons in the dentate gyrus thereby contributing to learning and memory. Here, we report that neurons together with neural stem and precursor cells secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this niche. EGFL7 knock-out in vivo promoted adult neurogenesis generating neurons forming additional spines which permanently integrated into the neural circuit until old age. RNA-sequencing identified the cytokine VEGF-D as a major molecular driver of this process in vivo. In behavioral studies EGFL7 knock-out mice displayed stronger maintenance of memory suggesting longer-lasting spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation in young and aged mice. Taken together, EGFL7 is an upstream regulator of the VEGF-D in adult neurogenesis and a key regulator of learning and memory.

neuroscience↗

bioRxiv2020

Functional microRNA targetome undergoes degeneration-induced shift in the retina

MicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases, including age-related macular degeneration, acting as post-transcriptional gene suppressors through their association with argonaute (AGO) protein family members. However, to understand their role in disease, investigation into the regulatory nature of miRNA with their targets is required. To identify the active-miRnome-targetome interactions in the degenerating retina, AGO2 HITS-CLIP was performed using a mouse model of retinal degeneration. Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed. This shift was also demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal miRNA loaded in AGO2. Following damage, AGO2 was localised to the inner retinal layers indicating a locational miRNA response to retinal damage. This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration.

molecular biology↗

bioRxiv2020

Exosomes and their miRNA cargo in retinal health and degeneration: mediators of homeostasis, and vehicles for targeted gene therapy.

1.1.PurposePhotoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases, however the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs including exosomes encapsulate and transfer nucleic acids, including microRNA (miRNA), to recipient cells which in disease may result in dysfunctional immune responses and a loss of homeostatic regulation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina. MethodsIsolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion. ResultsResults demonstrated an inverse correlation between s-mEV secretion and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage. ConclusionsTaken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.

molecular biology↗

bioRxiv2020

Multiple links between 5-methylcytosine content of mRNA and translation

5-methylcytosine (m5C) is a prevalent base modification in tRNA and rRNA but it also occurs more broadly in the transcriptome, including in mRNA, where it serves incompletely understood molecular functions. In pursuit of potential links of m5C with mRNA translation, we performed polysome profiling of human HeLa cell lysates and subjected RNA from resultant fractions to efficient bisulfite conversion followed by RNA sequencing (bsRNA-seq). Bioinformatic filters for rigorous site calling were devised to reduce technical noise. We obtained [~]1,000 candidate m5C sites in the wider transcriptome, most of which were found in mRNA. Multiple novel sites were validated by amplicon-specific bsRNA-seq in independent samples of either human HeLa, LNCaP and PrEC cells. Furthermore, RNAi-mediated depletion of either the NSUN2 or TRDMT1 m5C:RNA methyltransferases showed a clear dependence on NSUN2 for the majority of tested sites in both mRNAs and noncoding RNAs. Candidate m5C sites in mRNAs are enriched in 5UTRs and near start codons, and are commonly embedded in a local context reminiscent of the NSUN2-dependent m5C sites found in the variable loop of tRNA. Analysing mRNA sites across the polysome profile revealed that modification levels, at bulk and for many individual sites, were inversely correlated with ribosome association. Altogether, these findings emphasise the major role of NSUN2 in making this mark transcriptome-wide and further substantiate a functional interdependence of cytosine methylation level with mRNA translation.

molecular biology↗