Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1067837 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27688589_1.fastq.gz | Fastqsanger.gz | |||
| SRR27688589_2.fastq.gz | Fastqsanger.gz | |||
| SRR27688590_1.fastq.gz | Fastqsanger.gz | |||
| SRR27688590_2.fastq.gz | Fastqsanger.gz | |||
| SRR27688591_1.fastq.gz | Fastqsanger.gz |
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Project description:Acquired drug resistance is a major challenge for cancer therapy and the leading cause of cancer mortality. However, the mechanisms of drug resistance are diverse and the strategy to specifically target drug resistant cancer cells remains an unmet clinical issue. We establisheda32 colorectal cancer (CRC) PDO biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies34 revealed that chemo-resistant PDOs exhibited elevated expression of LGR4 and activationof the35 Wnt signaling pathway. Further, we performed antibody screening against LGR4 and selecteda36 monoclonal antibody (LGR4-mAb) that potently inhibited the LGR4/Wnt signaling. In drug resistant PDOs and xenograft models, treatment with LGR4-mAb significantly sensitizeddrug- 38 induced ferroptosis. Mechanistically, LGR4 dependent Wnt signaling transcriptionally up-regulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Targeting40 Wnt signaling by LGR4-mAb and by other modulators augments ferroptosis when co-administrated with chemotherapeutic agents. Finally, LGR4-mAb therapy was effective against other cancers that express high levels of LGR4. Collectively, our results demonstrate a new strategy to selectively activate ferroptosis and provide a new opportunity to fight refractoryand44 recurrent cancers.
2023-09-25 | GSE244082 | GEO
Project description:Acquired and primary therapy resistance remain a major hurdle in clinical treatment of multiple myeloma (MM). Despite the availability of broad spectrum anti-cancer drugs, most MM patients eventually relapse and become refractory to current treatments. Therefore, we explored whether therapy-resistant MM cells are sensitive to ferroptosis induction, an iron-catalyzed mode of cell death associated with increased lipid peroxidation. In this study, we exposed glucocorticoid-resistant MM1R and glucocorticoid-sensitive MM1S cells to ferroptosis inducers RSL3 and evaluated their transcriptional changes via RNA sequencing. Compared to untreated controls, ferroptotic RSL3-treated cells displayed a significant upregulation of genes involved in inflammation, kinase signaling, cellular stress, and cell death pathways. Pre-treatment with ferroptosis inhibitor Fer-1 partly reverted these RSL3-induced transcriptional changes and revealed that especially genes involved in metal binding, nuclear receptor signaling, chromatin remodeling, and gene transcription regulation are pivotal for ferroptosis induction. Overall, these findings suggest that ferroptosis effectively targets MM1 cells and that RSL3-mediated ferroptosis triggers similar oxidative stress and cell death pathways in both MM1R and MM1S cells, irrespective of their glucocorticoid-sensitivity status.
2021-11-08 | GSE182638 | GEO
Project description:HR+HER2- breast cancers resistant to palbociclib-hormone therapy displayed increased lipid uptake and expression of stress response proteins (GPX4, PSMA7), by adding ferroptosis inducers to palbocilib-fulvestrant combination therapy, tumor response was enhanced in three different pre-clinical models: resistant cells, xenografts and PDX.
2025-01-06 | GSE270021 | GEO
Project description:Ferroptosis, a cell death pathway driven by lipid peroxidation, is implicated in several human diseases including cancer. Although ferroptosis is entwined with apoptosis, it currently has no characteristic biomarkers or gene signature. In this project we established a continuous phenotypic gradient between ferroptosis and apoptosis and coupled it to transcriptomic and metabolomic landscapes. Omics and mechanistic studies revealed that ferroptosis was associated with enhanced MITF activity, lysosomal function, glutaminolysis, TCA cycle, and activation of ATF4, while its transition into apoptosis was attributed to enhanced ER-stress, ATF4/CHOP switch and PE/PC metabolic shift. The gradual ferroptosis-to-apoptosis transcriptomic landscape was used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization and datasets analysis of various ferroptotic and apoptotic responses revealed highly specific ferroptosis biomarkers, which were robustly validated in vitro and in vivo. A subset of the GGS was correlated with poor prognosis in breast cancer patients and in PDX models and was found to consist of different ferroptosis repressors, including PDAP1, whose knockdown suppressed breast tumor growth in a mouse model. Collectively, this study highlights molecular switches between ferroptosis and apoptosis, uncovering a highly prognostic predictive ferroptosis gene signature, pointing to a few ferroptosis repressors for targeted breast cancer therapy.
2024-03-07 | GSE235201 | GEO
Project description:Osteochondral defects (OCD) cannot be efficiently repaired due to the unique physical architecture and the pathological microenvironment including enhanced oxidative stress and inflammation. Conventional strategies, such as the control of implant microstructure or the introduction of growth factors, have limited functions failing to manage these complex environments. Here we developed a multifunctional silk-based hydrogel incorporated with metal-organic framework nanozymes (CuTA@SF) to provide a suitable microenvironment for enhanced OCD regeneration. The incorporation of CuTA nanozymes endowed the SF hydrogel with a uniform microstructure and elevated hydrophilicity. In vitro cultivation of mesenchymal stem cells (MSCs) and chondrocytes showed that CuTA@SF hydrogel accelerated cell proliferation and enhanced cell viability, as well as had antioxidant and antibacterial properties. Under the inflammatory environment with the stimulation of IL-1β, CuTA@SF hydrogel still possessed the potential to promote MSC osteogenesis and deposition of cartilage-specific extracellular matrix (ECM). The proteomics analysis further confirmed that CuTA@SF hydrogel promoted cell proliferation and ECM synthesis. In the full-thickness OCD model of rabbit, CuTA@SF hydrogel displayed successfully in situ OCD regeneration, as evidenced by micro-CT, histology (HE, S/O, and toluidine blue staining) and immunohistochemistry (Col I and aggrecan immunostaining). Therefore, CuTA@SF hydrogel is a promising biomaterial targeted at the regeneration of OCD.
2022-03-04 | PXD031852 |
Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.
2020-09-23 | GSE137946 | GEO
Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.
2021-02-08 | GSE162069 | GEO
Project description:Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.
2024-05-24 | GSE267823 | GEO
Project description:We formulate and analyse a mathematical model describing immune response to avasculartumour under the influence of immunotherapy and chemotherapy and their combinations aswell as vaccine treatments. The effect of vaccine therapy is considered as a parametricperturbation of the model. In the case of a weak immune response, neither immunotherapy norchemotherapy is found to cause tumour regression to a small size, which would be below theclinically detectable threshold. Numerical simulations show that the efficiency of vaccinetherapy depends on both the tumour size and the condition of immune system as well as on theresponse of the organism to vaccination. In particular, we found that vaccine therapy becomesmore effective when used without time delay from a prescribed date of vaccination after surgeryand is ineffective without preliminary treatment. For a strong immune response, our modelpredicts the tumour remission under vaccine therapy. Our study of successive chemo/immuno,immuno/chemo and concurrent chemoimmunotherapy shows that the chemo/immunosequence is more effective while concurrent chemoimmunotherapy is more sparing.
2020-01-14 | MODEL2001140002 | BioModels
Project description:Ferroptosis is a unique form of intracellular iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. GPX4, an antioxidant defense enzyme, plays a pivotal role as regulator of ferroptosis. Extensive researches suggest that targeting GPX4 holds promise for cancer therapy. However, the current GPX4 inhibitors face challenges due to unfavorable drug-like properties, which hinder their progress in clinical development. In this study, we identified a novel inhibitor called MI-2, demonstrating potent ferroptosis-inducing capacity. Mechanistically, MI-2 effectively inhibits the activity of GPX4 by direct interaction. Furthermore, MI-2 promotes the degradation of GPX4 through its well-established target, MALT1. In multiple cancer models, MI-2 has demonstrated synergistic effects when combined with sorafenib or regorafenib, resulting in enhanced ferroptosis induction. These findings highlight the dual modulatory effects of MI-2 on GPX4 activity and stability, offering a promising starting point for the development of drug-like GPX4 inhibitors with translational potential.
2024-01-27 | PXD048953 |