Biology subjects

Ziehm, M.

Publications and source records attributed to Ziehm, M..

4 recordsLinked to original sources

bioRxiv2024

Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the blood proteome

Cystic fibrosis (CF), resulting from a dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR), affects multiple organs through mucus obstruction and differences in secretion. The CFTR modulator drug combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, ETI) has markedly improved clinical symptoms, but its broader molecular and systemic effects remain to be fully elucidated. We employed mass spectrometry-based proteomics to compare the blood proteomes of CF patients treated with the earlier, less effective lumacaftor/ivacaftor (LUM/IVA) combination against those receiving the more potent ELX/TEZ/IVA therapy. Our analysis revealed both specific and common pharmacodynamic signatures associated with inflammation and metabolic processes under each treatment regimen. Notably, ELX/TEZ/IVA therapy exhibited more consistent alterations across patients that were directed towards profiles observed in healthy individuals. Furthermore, by comparing sputum and blood proteomes of ELX/TEZ/IVA treated patients we identified counter-directional changes in the pulmonary surfactant-associated protein B, SFTPB, a potential biomarker of lung tissue repair, which also correlated with lung function improvements. This study provides a comprehensive resource that enhances our understanding of CFTR modulator-driven proteome alterations, offering insights to both systemic and local protein regulation in CF. Our findings indicate that ELX/TEZ/IVA promotes broader systemic health improvements, providing critical insights that could shape future therapeutic strategies in CF.

molecular biology↗

bioRxiv2021

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

cancer biology↗

bioRxiv2021

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and to the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospo-proteomics profiles confirm the cell-specific feedback effects and synergy of MEK and IGFR targeted treatements. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies, and our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.

cancer biology↗

bioRxiv2016

Drug repurposing for ageing research using model organisms

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against ageing, despite many genes and pathways shown to be important in the ageing process and numerous studies demonstrating that genetic interventions can lead to a healthier ageing phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate ageing in the invertebrates C. elegans and Drosophila. Our approach combines information on genetic effects on ageing, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate ageing. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating ageing, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human ageing.

pharmacology and toxicology↗