FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA988473 | ENA |
REPOSITORIES: ENA
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Project description:Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.
| S-SCDT-10_1038-S44321-024-00090-6 | biostudies-other
Project description:Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.
| S-EPMC11251055 | biostudies-literature
Project description:Analysis of factors upregulated in highly aggressive 4T1 tumour cells compared to the less aggressive 4T07 tumour cells and the non-metastatic 67NR tumour cells at gene expression level. The question addressed in the present study was which metabolic pathways are differentially activated by these cells and therefore could account for the observed difference metastatic potential of these tumours. Results provide important characterisation of the ex vivo expression profiles of highly aggressive vs. non-aggressive tumour cells. 4T07 and 4T1 tumour cell data was previously published in GSE50471.
2024-05-13 | GSE236033 | GEO
Project description:Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in a variety of degenerative diseases and represents a targetable vulnerability in certain cancers. The ferroptosis-susceptible cell-state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions. Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify a key role for peroxisome–ether phospholipid genes in driving ferroptosis susceptibility and evasion in ovarian cancer.
2020-09-16 | GSE151062 | GEO
Project description:CDKN2A remodels lipid metabolism to prime glioblastoma for ferroptosis
| PRJNA965893 | ENA
Project description:CDKN2A remodels lipid metabolism to prime glioblastoma for ferroptosis
| PRJNA965892 | ENA
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
2021-10-09 | GSE160574 | GEO
Project description:Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron-dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
2025-01-13 | GSE286185 | GEO
Project description:To comprehensively identify RNA molecules that are naturally associated with cellular lipid components, we isolated lipid fractions and their bound RNAs from triple-negative breast cancer (TNBC) patient tissues. Fresh frozen TNBC tissues and their normal counterparts were subjected to total RNA extraction, or in parallel, to whole cell fractionation via Hydrostatic Pressure Cycling to form a lipid-containing upper phase, a denatured protein-containing lower phase, and an insoluble fraction containing DNA and RNA (PBI Inc.) The RNAs extracted from the lipid fractions were applied to LncRNA Array v3.0 (Arraystar).
2017-02-21 | GSE92414 | GEO
Project description:Disulfiram/Cu induce ferroptosis in triple-negative breast cancer cells
| PRJNA861174 | ENA