Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA764591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15970160.fastq.gz | Fastqsanger.gz | |||
| SRR15970161.fastq.gz | Fastqsanger.gz | |||
| SRR15970162.fastq.gz | Fastqsanger.gz | |||
| SRR15970163.fastq.gz | Fastqsanger.gz | |||
| SRR15970164.fastq.gz | Fastqsanger.gz |
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Project description:Necrosis is a common feature of most solid malignant tumors and a major consequence of chemotherapy. The debris released by necrotic cells includes many damage/danger-associated molecular patterns (DAMPs) that stimulate cell surface and intracellular pattern recognition receptors (PRRs) activation. Treatment of Ewing’s sarcoma with conventional chemotherapy has reached a plateau in efficacy. The inability to target the fusion protein responsible for its pathogenesis warrants the quest for alternative therapeutic strategies. We have shown that DAMPs released by necrotic cells can stimulate the growth of EwS cells cultured in 3D and that of the related tumors in vivo. In stark contrast, we observed that STING, a signaling platform that responds to nucleic acids released from damaged nuclei, opposed the effect of DAMPs on EwS cell growth in vitro and tumor growth in vivo, maintaining cholesterol homeostasis. Our observations suggest that STING activation in conjunction with cholesterol-reducing agents may offer an unsuspected approach to control EwS growth.
2021-12-27 | GSE184421 | GEO
Project description:Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.
| S-EPMC8742871 | biostudies-literature
Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae Trophoblastic debris were isolated by low speed centrifugation from three individual first trimester human placentae (three biological replicates). The protein content in trophoblastic debris was measured by BCA assay. HMEC-1 was co-cultured with trophoblastic debris (60ug/ml total debris protein contents) for either 2 or 21 hours before RNA extraction. Untreated HMEC-1 at 2 and 21 hours were used as controls.In total, 12 samples were analyzed.
2016-08-21 | E-GEOD-69996 | biostudies-arrayexpress
Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae
2016-08-21 | GSE69996 | GEO
Project description:To extend our understanding of systemic necrosis in susceptible potato tubers infected with the necrotic strain of Potato virus Y (PVYNTN) gene expression was compared between healthy and infected non-necrotic and necrotic (both non-necrotic and necrotic tissue) potato tubers.
2018-05-16 | E-MTAB-5776 | biostudies-arrayexpress
Project description:Small RNA sequencing on trophoblast debris samples was employed to profile the small RNA contents in either normotensive or preeclamptic trophoblast debris. We have identified 1278 miRNAs and 2646 non-miRNA small RNA fragments across all trophoblast debris samples. Differential expression analysis was executed by iSRAP small RNA sequencing analysis pipeline and we identified 16 miRNAs, 5 tRNA fragments from 3 different tRNAs, 13 snRNA fragments and 85 rRNA fragments differentially contained between preeclamptic and normotensive trophoblast debris
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Project description:The goal of this experiment was to determine differences in RNA expression between the central necrotic tumor core and the non-necrotic rim region in orthotopic xenograft models of 4T1 cells transplanted into immunocompromised rat hosts. These samples are derived from tissues obtained from 4T1 spheroids transplanted orthotopically into the mammary fat pads of SRG OncoRats. 4T1 cells were cultured as spheroids in suspension for 24-hours prior to transplantation in 2% matrigel. 600,000 cells in a 1:1 mixture of matrigel and DMEM/F12 were transplanted orthotopically into the right T4 fat pads of SRG rats. At day 27 post transplanation, primary tumors and lungs were collected. The primary tumors were cut in half to expose the cross-section, and the tumors were dissected to isolate the necrotic core region and the non-necrotic rim region. Samples were snap frozen and sent to Genewiz-Azenta for RNA extraction, library prep, and next-gen sequencing.
2024-01-01 | GSE223419 | GEO
Project description:The liver can fully regenerate after partial resection and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here we demonstrate that monocyte-derived macrophages (MoMFs) are rapidly recruited to and encapsulate necrotic areas during immune-mediated liver injury, and this feature is essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activate the JAG1-NOTCH2 axis to induce cell death-resistant SOX9+ hepatocytes near the necrotic lesions, which acts as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induces a cluster of C1q+MoMFs that promote necrotic removal and liver repair, while Pdgfb+MoMFs activate hepatic stellate cells (HSCs) to express a-smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions not only by removing necrotic tissues but also by inducing cell death resistant hepatocytes to form a perinecrotic capsule and by activating a-smooth actin expressing HSCs to facilitate necrotic lesion resolution.
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