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1.
Mol Oncol ; 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38590214

ABSTRACT

Ferroptosis is a newly identified iron-dependent type of regulated cell death that can also be regarded as death caused by the specific collapse of the lipid antioxidant defence machinery. Ferroptosis has gained increasing attention as a potential therapeutic strategy for therapy-resistant cancer types. However, many ferroptosis-inducing small molecules do not reach the pharmacokinetic requirements for their effective clinical use yet. Nevertheless, their clinical optimization is under development. In this review, we summarize the current understanding of molecular pathways regulating ferroptosis, how cells protect themselves from the induction of ferroptotic cell death, and how a better understanding of cancer cell metabolism can represent vulnerabilities for ferroptosis-based therapies. Lastly, we discuss the context-dependent effect of ferroptosis on various cell types within the tumor microenvironment and address controversies on how tissue ferroptosis might impact systemic cancer immunity in a paracrine manner.

2.
Nat Struct Mol Biol ; 30(11): 1618-1619, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37957304
3.
Cell Death Differ ; 30(2): 442-456, 2023 02.
Article in English | MEDLINE | ID: mdl-36443441

ABSTRACT

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRASG12D expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.


Subject(s)
Apoptosis Regulatory Proteins , Carcinogenesis , Ferroptosis , Animals , Humans , Mice , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Transformation, Neoplastic , Lung Neoplasms/genetics , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Apoptosis Regulatory Proteins/metabolism , Pancreatic Neoplasms
4.
Mol Cell Oncol ; 8(4): 1933871, 2021.
Article in English | MEDLINE | ID: mdl-34616869

ABSTRACT

Our recent study revealed that non-neuroendocrine small cell lung cancer (SCLC) is sensitive to the induction of ferroptosis due to upregulation of ether lipid synthesis. While neuroendocrine SCLC is ferroptosis resistant, it acquires addiction to the thioredoxin pathway. Combined redox pathway targeting therefore achieves efficient anti-tumor activity in heterogenous SCLC.

5.
Nat Commun ; 12(1): 2048, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33824345

ABSTRACT

Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.


Subject(s)
Ferroptosis , Neuroendocrine Tumors/pathology , Small Cell Lung Carcinoma/pathology , Animals , Antioxidants/metabolism , Apoptosis , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Survival , Humans , Lipid Metabolism , Male , Mice, Nude , Models, Biological , Necroptosis , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipids/metabolism , Prognosis , Thioredoxins/metabolism
6.
Cancers (Basel) ; 12(1)2020 Jan 09.
Article in English | MEDLINE | ID: mdl-31936571

ABSTRACT

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

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