Biology subjects

Braegelmann, J.

Publications and source records attributed to Braegelmann, J..

3 recordsLinked to original sources

bioRxiv2025

An integrated model of population growth saturation and basal ROS levels predicts cellular ferroptosis sensitivity

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and membrane rupture. While cellular populations reaching confluence are known to have limited sensitivity to ferroptosis, an understanding of the interplay between growth dynamics, ROS levels and ferroptosis is currently lacking. Here we use live-cell imaging coupled to ROS tracing to reveal a feedback loop between population growth and ferroptotic cell death. Starting out from the observation that the cellular proliferation rate declines with increased cellular density, we find that ROS levels also decline with increasing cellular density. Low ROS levels make cells insensitive to ferroptosis, which in turn enables population growth. This feedback produces two steady states: (i) a ferroptosis-insensitive state characterized by slow growth, low levels of ROS and low rates of cell death and (ii) a ferroptosis-sensitive state characterized by rapid growth, ROS accumulation, and high rates of ferroptosis. Interestingly, triggering effective ferroptosis by interfering with GPX4 activity is directly linked with this mechanism. On the other hand, keeping cell numbers and drug concentration/cell constant while restricting growth space led to reduced proliferation, reduced ROS and decreased ferroptotic cell death. Importantly, ferroptosis resistance at high cellular confluency could be broken by increasing cellular ROS and lipid ROS through a galactose-promoted OXPHOS switch. A mathematical model of the feedback mechanism predicts the long-term fate of populations as well as their ferroptosis sensitivity when external conditions impacting cell proliferation rates, ROS, or both are changed.

cancer biology↗

bioRxiv2025

ESM-Effect: An Effective and Efficient Fine-Tuning Framework towards accurate prediction of Mutation's Functional Effect

Predicting functional properties of mutations like the change in enzyme activity remains challenging and is not well captured by traditional pathogenicity prediction. Yet such functional predictions are crucial in areas like targeted cancer therapy where some drugs may only be administered if a mutation causes an increase in enzyme activity. Current approaches either leverage static Protein-Language Model (PLM) embeddings or complex multi-modal features (e.g., static PLM embeddings, structure, and evolutionary data) and either (1) fall short in accuracy or (2) involve complex data processing and pre-training. Standardized datasets and metrics for robust benchmarking would benefit model development but do not yet exist for functional effect prediction. To address these challenges we develop ESM-Effect, an optimized PLM-based functional effect prediction framework through extensive ablation studies. ESM-Effect fine-tunes ESM2 PLM with an inductive bias regression head to achieve state-of-the-art performance. It surpasses the multi-modal state-of-the-art method PreMode, indicating redundancy of structural and evolutionary features, while training 6.7-times faster. In addition, we develop a benchmarking framework with robust test datasets and strategies, and propose a novel metric for prediction accuracy termed relative Bin-Mean Error (rBME): rBME emphasizes prediction accuracy in challenging, non-clustered, and rare gain-of-function regions and correlates more intuitively with model performance than commonly used Spearmans rho. Finally, we demonstrate partial generalization of ESM-Effect to unseen mutational regions within the same protein, illustrating its potential in precision medicine applications. Extending this generalization across different proteins remains a promising direction for future research. ESM-Effect is available at: https://github.com/moritzgls/ESM-Effect.

bioinformatics↗

bioRxiv2024

Oncogenic RAS signaling suppresses ferroptosis via transcriptional upregulation of GCH1

Ferroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. The role of oncogenic RAS signaling in modulating the cellular response to ferroptosis is controversial. While seminal studies described that oncogenic RAS transformation drives a synthetic lethal vulnerability to archetypal ferroptosis inducers including erastin (eradicator of RAS and ST-expressing cells) and RSL3 (Ras selective lethal 3), more recent work suggest that oncogenic RAS signaling may confer ferroptosis resistance. Thus, the impact of oncogenic RAS expression on ferroptosis sensitivity is still poorly understood. Here, using orthogonal cellular systems across multiple classes of ferroptosis- inducing agents, as well as in silico therapeutic drug-response analyses, we provide unifying evidence that oncogenic RAS signaling suppresses ferroptosis. Integrated proteo- and transcriptomic analyses in oncogenic RAS-transformed cells further uncovered that RAS signaling upregulates the ferroptosis suppressor GTP cyclohydrolase I (GCH1) via transcriptional induction by the transcription factor ETS1 downstream of the RAS-MAPK signaling cascade. Targeted repression of Gch1 or of Gch1-controlled tetrahydrobiopterin (BH4) synthesis pathway is sufficient to sensitize RAS-mutant cell lines to ferroptosis in 2D and 3D cell models, as well as in tumor organoids and tumor xenografts, highlighting a mechanism through which RAS promotes resistance to ferroptosis induction. Furthermore, we found that GCH1 expression is clinically relevant and correlates with RAS signaling activation in human cancers. Overall, this study redefines oncogenic RAS signaling to be a ferroptosis suppressor, and identifies GCH1 as a mediator of this effect and a potential clinical target for the sensitization of RAS-driven cancers to ferroptosis-inducing agents. Significance StatementAlthough it is commonly accepted that ferroptosis induction is a mutant RAS-selective lethality, accumulating evidence suggests that oncogenic RAS protects cells against this form of cell death. However, a systematic survey establishing the relationship between RAS and ferroptosis sensitivity is lacking, and the molecular mechanisms this entails are still poorly understood. Here, we report across RAS-mutant isoforms, in diverse cellular models, and using multiple ferroptosis-inducing compounds that oncogenic RAS consistently suppresses ferroptosis. Further, we show that oncogenic RAS-mediated ferroptosis suppression is attributed to the upregulation of GCH1 and its downstream metabolite, tetrahydrobiopterin. Our study delivers a shift towards a new paradigm in which oncogenic RAS confers ferroptosis resistance, and a potential clinical strategy to re-engage ferroptosis sensitivity in RAS-driven cancers.

cancer biology↗