Fedorova
Friedmann Angeli
Brabletz / Brabletz
Conrad
Boettcher
Westermann
Alborzinia
Schulze
Muckenthaler
Dick
Garcia Saez
von Karstedt
Venkatarami
Friese / Woo
Todoran
Eurich / Kotsch
Krüger / Al Abdullah
HAMED ALBORZINIA
Exploring selenocysteine metabolism as a targeted therapy approach in cancer
Hamed Alborzinia, DKFZ Heidelberg
h.alborzinia[at]dkfz-heidelberg.de
2nd funding period:
`Exploring selenocysteine metabolism as a targeted therapy approach in cancer`
1st funding period:
`Characterization and exploitation of novel ferroptosis regulators to target MYCN amplified cancers`
JAN BÖTTCHER
Role of ferroptosis for regulation of anti-cancer immunity by dendritic cells
Jan Böttcher, Universität Tübingen
Jan.Boettcher@med.uni-tuebingen.de
2nd funding period:
`The role of PGE2 production by ferroptotic cancer cells for regulation of anti-cancer T cell immunity`
Stem-like TCF1+CD8+ T cells can drive immune responses to cancer through clonal expansion and effector differentiation within tumor tissue, which can be inhibited by tumour cell-derived factors such as prostaglandin E2 (PGE2). In this project, we aim to investigate how ferroptotic cancer cell death contributes to the regulation of stem-like T cell responses in tumours and to which extent it shapes the course of anti-cancer T cell immunity.
1st funding period:
`Role of ferroptosis for regulation of anti-cancer immunity by dendritic cells`
Dendritic cells are sentinel leukocytes with key roles in the initiation and regulation of immune responses. They have the ability to sense cell death in their environment and transmit this information to other leukocytes. In this project we aim to understand the mechanisms by which dendritic cells sense ferroptosis in the tumor microenvironment, how the interaction with ferroptotic cancer cells shapes dendritic cell function and to which extent this interplay impacts on anti-cancer immunity.
THOMAS BRABLETZ/SIMONE BRABLETZ
Zeb1-mediated mechanisms of the EMT-associated ferroptosis sensitivity
Thomas Brabletz, FAU, Erlangen
thomas.brabletz[at]fau.de
Simone Brabletz, FAU, Erlangen
simone.brabletz[at]fau.de
2nd funding period:
`Zeb1-mediated mechanisms of the EMT-associated ferroptosis sensitivity`
In contrast to apoptosis, the predominant death signalling pathway in differentiated (e.g. epithelial) cells, ferroptosis can be induced mainly in undifferentiated cells and cells with a (partial) mesenchymal phenotype. Tumour cells often acquire this phenotype that is associated with high metastatic capacity and resistance to therapy, through the activation of EMT-transcription factors like Zeb1. In this project, we investigate the different mechanisms of Zeb1 mediated ferroptosis sensitivity. In this regard, we have shown Zeb1 to shift the cellular phospholipid composition towards polyunsaturated fatty acids (PUFAs) and now focus on its pro-ferroptotic role in iron metabolism. Finally, we plan to utilize our findings as a basis for new strategies against highly aggressive, therapy-resistant tumours.
1st funding period:
`Zeb1-mediated control of the PUFA/MUFA ratio in EMT-associated ferroptosis sensitivity`
In contrast to apoptosis, the predominant death signalling pathway in differentiated (e.g. epithelial) cells, ferroptosis can be induced mainly in undifferentiated cells and cells with a (partial) mesenchymal phenotype. In tumour cells, this phenotype is often acquired through the activation of an EMT, and is associated with high metastatic capacity and resistance to therapy. In this project, we will investigate the role of the EMT transcription factor Zeb1 for the expression of polyunsaturated fatty acids (PUFAs) and the associated ferroptosis sensitivity, and use it as a basis for new strategies against highly aggressive, therapy-resistant tumours.
MARCUS CONRAD
Development of a lipid-based ferroptosis biomarker for the study of neurodegenerative disease
Marcus Conrad, Helmholtz Zentrum München
marcus.conrad[at]helmholtz-muenchen.de
2nd funding period:
`Neuro-glial crosstalk during ferroptosis`
Ferroptosis is a regulated form of necrotic cell death driven by lipid peroxidation and increasingly linked to neurodegenerative diseases (NDs) such as Alzheimer’s. Despite their growing prevalence, no curative treatments for NDs exist. Deletion of the ferroptosis regulator GPX4 in mouse neurons leads to neuroinflammation and cognitive decline, resembling human pathology. A rare GPX4 variant causes Sedaghatian-type spondylometaphyseal dysplasia (SMDS), marked by neurodegeneration. To uncover ferroptosis-related mechanisms, we aim to identify transcriptomic and lipidomic signatures, focusing on neuron-glial interactions. A novel SMDS mouse model will help study GPX4-related neuroprotection and test therapeutic strategies for currently untreatable NDs.
1st funding period:
`Development of a lipid-based ferroptosis biomarker for the study of neurodegenerative disease`
Ferroptosis is a metabolic form of cell death characterized by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis underlies numerous degenerative diseases including tissue ischemia/reperfusion injury and certain neurodegenerative diseases. Although key players of ferroptosis and ferroptosis modulating agents have been identified in recent years, a robust lipid-based ferroptosis biomarker is still lacking. Thus, we will perform a comprehensive and comparative (epi)lipidomics analysis of mice lacking GPX4 in distinct neuronal subpopulations of the brain and of samples from patient suffering from neurodegenerative disease. The identification and validation of a lipid-based ferroptosis-specific biomarker will be key not only in understanding the role of ferroptosis in neurodegenerative disease progression, but also essential for measuring therapy success using novel ferroptosis-based pharmacotherapies currently under development.
TOBIAS D. DICK
Role and regulation of subcellular membrane lipid peroxidation in ferroptosis
Tobias D. Dick, DKFZ Heidelberg
T.Dick[at]dkfz-heidelberg.de
https://www.dkfz.de/en/redoxregulation/index.php
2nd funding period:
`Role and regulation of subcellular membrane lipid peroxidation in ferroptosis`
Increasing evidence suggests that the role of ferroptosis promoting and inhibiting factors depends on the subcellular site of lipid peroxidation (LPO). In this project we develop and use chemo- and optogenetic tools, targeted to specific subcellular membranes for generating radicals or singlet oxygen, in order to trigger LPO in a highly localized manner. We aim to define the role of individual ferroptosis inhibiting pathways for different endomembrane locations. For example, we ask how persulfides generated from different sources and subcellular locations differ in providing protection to specific organellar membranes.
1st funding period:
`Regulation of lipid peroxidation and ferroptosis by per- and polysulfides`
This project will explore possible connections between sulfane sulfur species (per- and polysulfides), lipid peroxidation and ferroptosis. Cells produce per- and polysulfides endogenously, by several enzymatic pathways and mechanisms, especially when they are under oxidative stress. Numerous studies, including our own, support the notion that sulfane sulfur species exhibit significant anti-oxidative and cytoprotective properties. We aim to investigate the hypothesis that biologically relevant sulfane sulfur species protect membranes against lipid peroxidation, and thus modulate ferroptosis sensitivity.
DENNIS EURICH / KATJA KOTSCH
Role of Metabolism-induced Ferroptosis Following Solid Organ Transplantation and its Implication for Allograft Survival
Katja Kotsch, Charité – Universitätsmedizin Berlin
katja.kotsch[at]charite.de
Dennis Eurich, Charité – Universitätsmedizin Berlin
dennis.eurich[at]charite.de
2nd funding period:
`Role of Metabolism-induced Ferroptosis Following Solid Organ Transplantation and its Implication for Allograft Survival`
Despite the advancement in short-term allograft survival over the past few decades, approximately 25% of patients still encounter graft failure within five years following transplantation. Furthermore, there is an urgent necessity to address the escalating disparity between patients on waiting lists and available donor organs. While the inhibition of ferroptosis holds promise in contexts of acute kidney injury or ischaemia reperfusion injury, there is a paucity of knowledge regarding ferroptosis mechanisms in the alloimmune response following solid organ transplantation. The objective of this study is to comprehend and manipulate the function of ferroptosis within the intricate system of intra-graft immune cells following solid organ transplantation. This knowledge is intended to enhance long-term allograft survival and the process of transplantation tolerance.
MARIA FEDOROVA
Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme
Maria Fedorova, Technical University of Dresden
maria.fedorova[at]tu-dresden.de
2nd funding period:
`Role of cells and tissues microenvironment in lipid metabolism and signaling in ferroptosis`
1st funding period:
`Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme`
Numerous studies clearly established that lipid metabolism and specific composition of cellular and tissue lipidomes determine ferroptosis sensitivity or resistance. To this end, a deeper understanding of lipid metabolism and oxidation at lipid species molecular level is required to predict ferroptosis sensitivity and propose relevant metabolic pathways as a potential pharmacological targets for pro- and anti-ferroptotic therapies. The proposed project aims to expand current understanding on the role of lipid metabolism in ferroptosis by mapping dynamics of lipidome remodeling and oxidation upon induction and execution of ferroptotic cell death at cellular and subcellular levels, and exploring modulatory potential of lipid metabolism by targeting lipid class and type specific pathways.
JOSÉ PEDRO FRIEDMANN ANGELI
Selenocysteine metabolism as a new target for ferroptosis induction
José Pedro Friedmann Angeli, Universität Würzburg
pedro.angeli[at]virchow.uni-wuerzburg.de
2nd funding period:
`Selenium metabolism and its contribution to ferroptosis resistance`
Ferroptosis offers a promising strategy for targeting cancer cells dependent on the selenoprotein GPX4. The lack of specific GPX4 inhibitors effective in vivo poses a challenge in translating ferroptosis-based therapies to clinical use. Our proposed approach addresses this challenge by targeting selenocysteine metabolism, a rare amino acid crucial for GPX4 function. In our initial funding period, we demonstrated the potential benefits of targeting this pathway in MYCN-amplified neuroblastoma models. Our strategy involves a combination of cellular and biochemical methods to thoroughly understand selenocysteine mobilization mechanisms in cells. Additionally, through structural characterization of key pathway components, we aim to gain molecular insights into selenium utilization and identify novel small molecules targeting this pathway.
1st funding period:
`Selenocysteine metabolism as a new target for ferroptosis induction`
Targeting the selenoprotein GPX4 has attracted considerable interest for the treatment of therapy refractory tumours. Yet, specific properties of the enzyme have hindered the development of pharmacological strategies for the induction of GPX4-based ferroptosis. In the present application we propose to explore the metabolism of the rare amino acid selenocysteine (Sec) to indirectly influence the activity of GPX4. Using a mixture of in vitro and in vivo models in combination with genetic screenings, we aim to identify critical mechanism of Sec mobilization and establish novel targets for the induction of ferroptosis.
MANUEL A. FRIESE / MARCEL S. WOO
Regulators of inflammation-induced ferroptosis in neurons
Manuel A. Friese, Universitätsklinikum Hamburg-Eppendorf
manuel.friese[at]zmnh.uni-hamburg.de
Marcel S. Woo, Universitätsklinikum Hamburg-Eppendorf
2nd funding period:
`Regulators of inflammation-induced ferroptosis in neurons`
Multiple sclerosis (MS) is a devastating autoinflammatory disease of the central nervous system that results in neurological impairments and is driven by inflammation-induced neurodegeneration. We aim to investigate how lipid peroxidation and ferroptosis contribute to neuronal loss in MS. To achieve this, we will take a two different approachs. First, we will employ a hypothesis-driven strategy to further examine the differential roles of established ferroptosis regulators in neurons. Second, we will conduct unbiased pharmacological and genetic screenings to identify novel regulators of inflammation-induced ferroptosis. These newly identified regulators will be subjected to functional and phenotypic analyses to enhance our understanding of neuronal ferroptosis and facilitate the development of novel therapeutic strategies to counteract MS-related neurodegeneration.
Intstitute website: www.inims.de
Twitter/X: @inims_hamburg
ANA J GARCÍA-SÁEZ
The wave of death: ferroptosis propagation from single cell death to tissue damage
Ana J. García-Sáez, Max Planck Institute of Biophysics
ana.garcia[at]biophys.mpg.de
Institute website: https://www.biophys.mpg.de/membrane-dynamics
2nd funding period:
The wave of death: ferroptosis propagation from single cell death to tissue damage
Ferroptosis is a form of regulated necrosis characterized by the iron-dependent accumulation of lipid peroxides in cellular membranes. During the first funding period, we characterized the membrane alterations in model membrane systems of lipid oxidation and cells undergoing ferroptosis in connection to membrane permeabilization and cell death. Using a novel optogenetic system for light-controlled ferroptosis induction, we also found that lipid peroxidation and cell death can propagate to nearby untreated cells through their closely apposed plasma membranes, in line with a wave-like pattern of ferroptosis progression observed in cell culture. Taking advantage of this unique tool, the overarching goal of this project is to gain new insight into how ferroptosis propagates between neighboring cells. We will first determine how the oxidative signals and the alterations in biophysical membrane properties are spread to neighboring cells upon optogenetic ferroptosis induction in selected cells. We will also define the role of cell-cell contacts in ferroptosis propagation and explore how they can be exploited for the regulation of ferroptosis spread. Finally, we will study ferroptosis propagation between cells of different type and in 3D tissues. The results will shed new light on the molecular mechanisms involved in the intercellular propagation of ferroptosis establishing a mechanistic link between cell-cell contacts and ferroptosis spread across diseased tissues.
1st funding period:
Membrane alterations in ferroptosis: from lipid oxidation to pore formation
The overarching goal of this project is to understand how lipid peroxidation triggers plasma membrane permeabilization leading to cell death. We previously found that the final step of ferroptosis execution involves the opening of nanopores at the plasma membrane that cause sustained high cytosolic calcium and cell swelling prior to cell death (Pedrera et al., 2019). Building on these results and our expertise on characterizing membrane permeabilization mechanisms in regulated cell death, we will determine the alterations in the biophysical properties of cellular membranes in ferroptotic cells using advanced microscopy and biophysical tools. We will then validate the functional relevance of previously known and newly identified lipid species for ferroptotic death and relate them to the membrane alterations identified . The expected outcome of this research will advance our molecular understanding of ferroptosis by establishing a mechanistic link between lipid peroxidation and execution of cell death.
SILVIA VON KARSTEDT
Consequences of cPLA2α-mediated ferroptosis regulation in small cell lung cancer (SCLC)
Silvia von Karstedt, CECAD Köln
2nd funding period:
`cPLA2α-mediated ferroptosis regulation in small cell lung cancer (SCLC)`
Small cell lung cancer (SCLC) is amongst the most aggressive forms of lung cancer with a very poor survival rate due to rapidly emerging chemotherapy resistance. Previously, we identified non-neuroendocrine (non-NE) SCLC to be exquisitely sensitive to ferroptosis while upon NE transdifferentiation/plasticity SCLC became ferroptosis resistant. Moreover, we defined a first atlas of ferroptotic secretomes capable of promoting macrophage priming. In addition, we previously found that during ferroptosis there is an early calcium influx preceding cell death. Recently, we found that cPLA2α expression is highly upregulated in ferroptosis sensitive human and mouse non-NE SCLC and promotes faster kinetics of ferroptotic cell death through the generation of free arachidonic acid (AA). Based on these data, with this proposal we aim to comprehensively discern how AA flux influences ferroptosis kinetics in cellular models of SCLC subtype heterogeneity and plasticity.
1st funding period:
`Consequences of cPLA2α-mediated ferroptosis regulation in small cell lung cancer (SCLC)`
Small cell lung cancer (SCLC) is amongst the most aggressive forms of lung cancer with a very poor survival rate due to rapidly emerging chemotherapy resistance. Recently, we identified non-neuroendocrine (non-NE) SCLC to be exquisitely sensitive to ferroptosis due to a rewired lipidome. Interestingly, in this subtype we find elevated expression of cytosolic phospholipase2 α (cPLA2α) and its inhibition to block ferroptosis induction. Therefore, as part of this consortium we aim to comprehensively characterise the role of cPLA2α in regulating ferroptosis and cancer-associated inflammation in SCLC.
ELKE KRUEGER / RUBA AL ABDULLAH
Deciphering the link between proteostatic control by the ubiquitin-proteasome system and ferroptosis in lymphocytes
Elke Krüger, University of Greifswald
elke.krueger[at]med.uni-greifswald.de
Ruba al Abdullah, University of Greifswald
Ruba.AlAbdulla[at]med.uni-greifswald.de
2nd funding period:
`Deciphering the link between proteostatic control by the ubiquitin-proteasome system and ferroptosis in lymphocytes`
In this project we will tackle the unresolved questions how the UPS-dependent proteostatic control is linked to ferroptosis and how sensing of proteotoxic stress impacts the immunogenicity of ferroptotic cell death. We will define how specific components of the UPS, such as the ubiquitin activating enzyme E1, certain E3 ligases or proteasome isoforms render cells susceptible to ferroptosis. We will further investigate proteotoxic stress responses and the involvement of their components in ferroptosis, and determine the intricate interplay between ferroptosis and proteotoxic stress-driven ICD.
MARTINA MUCKENTHALER
Iron-induced pancreatic ferroptosis: Deciphering underlying mechanisms and clinical implications for iron overload disorders
Martina Muckenthaler, Universität Heidelberg
Martina.Muckenthaler[at]med.uni-heidelberg.de
2nd funding period:
`Iron-induced pancreatic ferroptosis: Deciphering underlying mechanisms and clinical implications for iron overload disorders`
Ferroptosis is defined as an iron-dependent form of regulated cell death associated with the lethal accumulation of lipid-based reactive oxygen species (ROS). The aim of our project is to understand how iron impacts on ferroptosis selectively in some tissues (i.e. the pancreas) and not others (i.e. the liver) in a mouse model of iron overload disease. We showed that the vulnerability of the pancreas to ferroptosis is explained by a reduced capacity to export iron and weaker defenses against oxidative stress. Our research is currently focusing on the role of GPX4 in iron-induced pancreatic dysfunction and the identification of anti-ferroptosis therapies to protect tissues from ferroptosis in iron overload disorders.
1st funding period:
`Mechanisms of organ resistance and susceptibility to ferroptosis in a disease model of iron overload`
Ferroptosis is defined as an iron-dependent form of regulated cell death leading to the lethal accumulation of lipid-based reactive oxygen species (ROS). The aim of our project is to understand how iron impacts on ferroptosis and viability in a mouse model of iron overload disease. We aim to identify mechanisms that protect or sensitize organs for iron-induced damage. We will compare molecular signatures of iron-induced ferroptosis with “classic” ferroptosis. The results will help to determine which of the anti-ferroptosis therapies currently in development may be applicable to prevent tissue damage in iron overload disorders.
ALMUT SCHULZE
Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer
Almut Schulze, DKFZ Heidelberg
almut.schulze[at]dkfz-heidelberg.de
https://www.dkfz.de/tumor-metabolismus-und-microenvironment
2nd funding period:
`Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer`
Ferroptosis is a regulated form of cell death driven by the accumulation of lipid hydroperoxides in polyunsaturated fatty acids of cell membranes. These lipids derive from essential omega‑6 and omega‑3 fatty acids, which also generate bioactive molecules that promote inflammation and immune evasion in cancer. To survive, cancer cells rely on antioxidant systems that prevent lipid peroxidation, particularly GPX4, which requires glutathione. Because liver tissue contains little extracellular cystine, metastatic cancer cells must secure alternative cystine sources to avoid ferroptosis. This project investigates how essential fatty acid metabolism and cysteine‑scavenging mechanisms shape ferroptosis sensitivity, tumour progression and immune evasion in cancer.
1st funding period:
`Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer`
Ferroptosis plays an important role in cancer, as the activation of oncogenic signalling pathways and the enhanced metabolic activity of cancer cells causes oxidative stress that leads to enhanced peroxidation of PUFA-containing lipids. PUFA are precursors of lipid mediators to promote migration, angiogenesis and immune evasion, making cancer cells highly dependent on mechanisms that prevent ferroptosis. Consequently, triggering ferroptosis could be a promising strategy for cancer treatment. We are studying how oncogene-driven alterations in lipid metabolism affect ferroptosis sensitivity in cancer cells and how this is affected by different metabolic microenvironments to uncover novel mechanisms of ferroptosis regulation and identify potential targets for therapeutic intervention.
IOANA TODORAN, née Stejerean
Harnessing ferroptosis as a potential therapeutic target against melanoma-associated central nervous system metastases
Ioana Todoran, née Stejerean, University Medical Center Göttingen
ioana.stejerean[at]med.uni-goettingen.de
2nd funding period:
`Harnessing ferroptosis as a potential therapeutic target against melanoma-associated central nervous system metastases`
Melanoma distant metastases are particularly reliant on redox regulation for survival and drug resistance. However, it is scarcely known how metastatic melanoma cells control their redox homeostasis and thereby ferroptosis to evade systemic therapies. Our preliminary data indicate that melanoma brain metastasis (MBM) cells are more vulnerable to ferroptotic cell death than their extracranial counterparts and that this susceptibility is dependent on ACSL4 and FDFT1. Therefore, we aim to investigate the importance of ACSL4 and FDFT1 in MBM aggressive behavior and their therapeutic relevance.
VIVEK VENKATARAMANI
Molecular Exploitation of Amyloid Precursor Protein as Novel Ferroptosis Regulator
Vivek Venkataramani, Universität Würzburg
venkataram_v@ukw.de
1st funding period:
`Molecular Exploitation of Amyloid Precursor Protein as Novel Ferroptosis Regulator`
APP is widely known as precursor of neurotoxic Ab in Alzheimer disease (AD). However, the physiological function of the full-length protein is still debatable. Herein, we show that oncogene-mediated malignant transformation can induce APP biosynthesis. This confers an adaptive survival advantage for cancer cells, likely by preventing a pro-ferroptotic state. Moreover, APP is commonly overexpressed in various aggressive tumor types correlating with poor prognosis, and thus may represent an attractive target for cancer therapy. Mechanistically, loss-of-APP results in mitochondrial translocation and enzymatic activation of heme oxygenase-1 (HO-1). Systematic analysis of downstream pathways identified the heme-regulated transcription factor BACH1 as a central node that controls responses to oxidative stress and simultaneously enforces glycolytic energy supply resulting in polyunsaturated fatty acids (PUFA) accumulation. Our data demonstrate that inhibition of APP expression enhances BACH1-mediated ferroptosis, which significantly contributes to suppression of tumor growth and metastatic colonization in vivo. Thus, APP and APP-dependent downstream pathways offer new potential therapeutic targets to modulate ferroptosis-induced tumor suppression and other ferroptosis-disease-relevant settings.
FRANK WESTERMANN
Ferroptosis induction as a novel treatment concept for relapsed childhood cancers
Frank Westermann, DKFZ Heidelberg
f.westermann[at]kitz-heidelberg.de
2nd funding period:
`Ferroptosis induction as a novel treatment concept for relapsed childhood cancers`
Neuroblastoma, a childhood tumour of the sympathetic nervous system, shows strong clinical heterogeneity, with outcomes ranging from spontaneous regression to therapy‑refractory progression. High‑risk disease is commonly driven by MYCN amplification, TERT rearrangements or ATRX mutations. We previously found that a subset of MYCN‑amplified neuroblastoma cells is highly cystine‑dependent and sensitive to ferroptosis inducers due to reduced cysteine/glutathione availability. However, MYCN or GPX4‑related activity alone does not reliably predict ferroptosis sensitivity, suggesting additional protective mechanisms. Our data indicate that the GCH1‑BH4‑DHFR pathway and the FSP1‑CoQ axis strongly suppress lipid peroxidation. We will define how these systems cooperate and test combined targeting strategies, alongside establishing biomarkers predicting ferroptosis sensitivity in neuroblastoma and other childhood cancers.
1st funding period:
`Ferroptosis induction as a novel treatment concept for relapsed childhood cancers`
A substantial number of cancer cells are susceptible to ferroptosis. The lack of a more mechanistic understanding of this process yet precludes a systematic exploitation of this vulnerability as a therapeutic modality for cancer. Using childhood neuroblastoma as a model, we found that high MYCN oncoprotein activity induces addiction to the amino acid cysteine, and sensitizes to ferroptosis. The main research goal of this project is to develop a mechanistic model that rationalizes the impact of cyst(e)ine uptake, cysteine synthesis via transsulfuration and cysteine catabolism on the activity of the glutathione-GPX4 system controlling ferroptosis in ferroptosis-sensitive vs. resistant cancer cells.
