Ontology highlight
ABSTRACT:
PROVIDER: PRJNA942499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23756858_1.fastq.gz | Fastqsanger.gz | |||
| SRR23756858_2.fastq.gz | Fastqsanger.gz | |||
| SRR23756859_1.fastq.gz | Fastqsanger.gz | |||
| SRR23756859_2.fastq.gz | Fastqsanger.gz | |||
| SRR23756860_1.fastq.gz | Fastqsanger.gz |
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Project description:Most genetic events that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non-genetic mechanisms that drive these processes. Here, we performed in vivo gain-of-function CRISPR screens and identified SMAD3, BIRC3 and SLC9A5 as key drivers of BRAFi-resistance and the tumor growth capability of persister cells. We show that their expression levels increase during acquisition of BRAFi-resistance, and remain high in persister cells and during relapse. Critically, chemical inhibition of SMAD3 or BIRC3 efficiently abrogates melanoma tumor growth and persister cells proliferation. Genetic inhibition of these targets efficiently restored the sensitivity of persister cells to BRAFi. Our work expands our understanding of the biology of persister cells and highlight novel drug vulnerabilities that can be exploited to develop long-lasting anti-melanoma therapies.
2021-02-03 | E-MTAB-8595 | biostudies-arrayexpress
Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.
2025-07-14 | GSE300960 | GEO
Project description:Membrane protection against oxidative damage is tightly buffered by glutathione peroxidase 4 (GPX4), and endogenous radical-trapping antioxidants such as ubiquinone, vitamin E and K. Deficiencies in these protective systems have been linked to the accumulation of phospholipid peroxidation and ferroptosis induction. Recently, ferroptosis suppressor protein 1 (FSP1) was identified as a key player in this process, preventing phospholipid peroxidation and ferroptosis by regenerating radical-trapping antioxidants. Yet, regulators of FSP1 have remained largely unknown, and their identification is critical for understanding the mechanism regulating phospholipid peroxidation and ferroptosis. In this study, we conducted a CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying vitamin B2 (riboflavin) as a yet-unaccounted modulator of ferroptosis sensitivity. We demonstrate that vitamin B2, unlike other vitamins that directly act as radical-trapping antioxidants, facilitates the recycling of lipid-soluble antioxidants by directly supporting FSP1 stability and activity, thereby mitigating phospholipid peroxidation. Thus, we uncovered a direct role of vitamin B2 in maintaining membrane integrity and supporting membrane tolerance to lipid peroxidation and ferroptosis resistance. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway, with potential implications for treating cancer and other diseases where ferroptosis plays a pivotal role.
2025-10-31 | PXD061038 | Pride
Project description:Triggering ferroptosis has recently been demonstrated to be a promising approach for cancer treatment. However, the application of current ferroptosis inducers, such as GPX4 inhibitors, was rather limited due to their pharmaceutical or safety issues, which evoking the discovery of new favorable candidates. In this study, we took advantage of a phenotypic screening strategy and discovered (20S)-Protopanaxatriol (hereafter as (20)S-APPT), a derivative of ginsenosides, as a novel ferroptosis inducer both in vitro and in vivo, with desirable safety in particular. Mechanistic investigations revealed that (20)S-APPT induces ferroptosis by targeting plasma-membrane localized CoQ10 oxidoreductase FSP1. Upon FSP1 inhibition, oxidation of arachidonic acid in an ACSL4 dependent way as well as reactive oxygen species produced by mitochondrial oxidative stress are both involved to boost the process of ferroptosis. Intriguingly, we firstly uncovered that inhibition of FSP1 alone is sufficient to induce ferroptotic cell death in a subset of liver and bile duct cancer cells. Furthermore, we unexpectedly found that only the addition of GCS inhibitor BSO, which attenuates intracellular GSH, exerts synergistic effect to induce ferroptosis with FSP1 inhibitors in rest non-responsive cancer cells, while sparing normal cell counterparts intact. Overall, our work helped to gain insights into a new ferroptotic role of FSP1 and further proposed that co-targeting FSP1 and GCS is a hopeful and safe strategy to combat liver and bile duct cancer through triggering ferroptosis, which might facilitate to pave a new way for drug development and further clinical therapeutic intervention in the future.
2025-12-09 | GSE284669 | GEO
Project description:Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione and various ferroptosis suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is downregulated in multiple persister cell types and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely upon residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition downregulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induce reactive oxygen species and sensitize multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
2025-11-10 | GSE303411 | GEO
Project description:We conducted a proteomic interactome analysis of well-known regulators of ferroptosis, ACSL4, LPCAT3, ALOX12, ALOX15, PEBP1, NCOA4, GCH1, FSP1, DHODH, SLC7A11, GCLC, GCLM, GSS, and GPX4. Take LPCAT3 as an example, we uncovered an opposing role of its binding protein CEPT1 in suppressing ferroptosis.
2024-10-17 | PXD035146 | Pride
Project description:Ferroptosis therapy has been well-established in various cancers; however, colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the use of ferroptosis therapy in CRC. Through drug screening, we found histone deacetylase inhibitor (HDACi) significantly sensitized ferroptosis. Mechanically, HDACi reduced FSP1 by promoting its mRNA degradation, a known ferroptosis defense molecular. In further research, we confirmed that HDACi specifically targeted HDAC1 and suppressed the H3K27ac modification of FTO and ALKBH5. The activation of FTO and ALKBH5 resulted in a reduction of N6-methyladenosine (m6A) modification on FSP1 mRNA, leading to its degradation and ultimately sensitizing CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically reduced CRC both in vivo and in vitro. In conclusion, our research reveals how HDACi sensitized ferroptosis and prompts the combination of HDACi/ferroptosis inducers as a promising therapeutic strategy for solid tumors.
2025-04-03 | GSE263463 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance.
2024-05-21 | GSE235336 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. Therefore, unravelling the underlying mechanisms responsible for reduced sensitivity to ferroptosis inducers, such as erastin or RSL3, may pave the way for designing effective therapeutic regimens for PDAC patients.
2024-05-21 | GSE235333 | GEO
Project description:We discovered, through untargeted metabolomics, that creatine promotes ferroptosis in colorectal cancer. Our study identifies ERK2 as a creatine sensor that mediates active FSP1 and ferroptosis resistance, and highlights the potential of targeting tumor SLC6A8 for cancer treatment.
2025-09-05 | GSE285466 | GEO