Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA927037 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23214200.fastq.gz | Fastqsanger.gz | |||
| SRR23214201.fastq.gz | Fastqsanger.gz | |||
| SRR23214202.fastq.gz | Fastqsanger.gz | |||
| SRR23214203.fastq.gz | Fastqsanger.gz | |||
| SRR23214204.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 105 |
Similar Datasets
Project description:Interleukin-2 (IL-2) is a fundamental cytokine that controls the proliferation and differentiation of T cells1. Its direct administration in vivo has conferred durable, complete responses in patients with metastatic melanoma and renal cell cancer, while it is also used to expand tumor-infiltrating lymphocytes (TILs) in vitro for adoptive cell therapy (ACT)2. Unfavorable properties of IL-2 including terminal differentiation of effector T cells3-6, induction of activation-induced cell death (AICD)2, 7, 8, expansion of regulatory T (Treg) cells, and toxicity at high doses, have driven the development of IL-2 variants with modified biological properties9-13. However, how cytokine modifications alter cell fate decisions is not well understood. Here, taking a systems biology approach we have comprehensively elucidated how a non CD25-binding, IL-2-biased agonist (IL-2v)14 reprograms signaling, transcriptional, and metabolic networks of CD8+ T cells in vitro to favor stemness while simultaneously driving expansion and functionality. Such "expansion-stemness state" defines metabolically fit CD8+ T cells capable of superior persistence and tumor control. These findings broaden our fundamental understanding of the effects of IL-2v on T-cell biology and provide an investigational framework for the rational development and evaluation of cytokine variants with clinical relevance.
2025-01-01 | GSE223651 | GEO
Project description:Synonymous recoding of viral genome can attenuate their replication, but can have pleiotropic effects, with multiple mechanisms contributing to attenuation. We set out to design recoded viral genomes whose attenuation was specific and conditional. The zinc finger antiviral protein (ZAP) recognizes CpG dinucleotides and targets CpG-rich RNAs for depletion, but RNA features such as CpG numbers, spacing and surrounding nucleotide composition that enable specific modulation by ZAP are undescribed. Using synonymously mutated HIV-1 genomes, we define several sequence features that govern ZAP sensitivity and stable attenuation. Using features defined using HIV-1, we then designed a mutant enterovirus A71 genome whose attenuation was also stable and strictly ZAP-dependent, both in cell culture and in mice. This conditionally attenuated enterovirus A71 elicited neutralizing antibodies that were protective against wild-type enterovirus 71 infection and disease. Elucidation of the determinants of ZAP sensitivity can thus enable the rational design of conditionally attenuated viral vaccines.
2022-07-26 | GSE208611 | GEO
Project description:RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design
| PRJNA860213 | ENA
Project description:Fractionated irradiation of breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype
| PRJNA783278 | ENA
Project description:Background & aimsAmong the reprogrammed metabolic pathways described in cancer stem cells, aberrant lipid metabolism has recently drawn increasing attention. Our study explored the contribution of fatty acids (FA) in the regulation of stem-like features in intrahepatic cholangiocarcinoma (iCCA).MethodsWe previously identified a functional stem-like subset in human iCCA by using a three-dimensional sphere (SPH) model in comparison to parental cells grown as monolayers (MON). In this study, quantification of intracellular free FA and lipidomic analysis (triacylglycerol [TAG] composition, de novo synthesis products) was performed by Liquid chromatography-mass spectrometry (LC-MS); quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS), respectively, in both SPH and MON cultures.ResultsStem-like SPH showed a superior content of free FA (citric, palmitic, stearic, and oleic acids) and unsaturated TAG. Molecularly, SPH showed upregulation of key metabolic enzymes involved in de novo FA biosynthesis (AceCS1, ACLY, ACAC, FASN, ACSL1) and the mTOR signalling pathway. In patients with iCCA (n = 68), tissue expression of FASN, a key gene involved in FA synthesis, correlated with 5-year overall survival. Interference with FASN activity in SPH cells through both specific gene silencing (siRNA) or pharmacological inhibition (orlistat) decreased sphere-forming ability and expression of stem-like markers. In a murine xenograft model obtained by injection of iCCA-SPH cells, FASN inhibition by orlistat or injection of FASN-silenced cells significantly reduced tumour growth and expression of stem-like genes.ConclusionAltered FA metabolism contributes to the maintenance of a stem-like phenotype in iCCA. FASN inhibition may represent a new approach to interfere with the progression of this deadly disease.Impact and implicationsRecent evidence indicates that metabolic disorders correlate with an increased susceptibility to intrahepatic cholangiocarcinoma (iCCA). Our investigation emphasises the pivotal involvement of lipid metabolism in the tumour stem cell biology of iCCA, facilitated by the upregulation of crucial enzymes and the mTOR signalling pathway. From a clinical perspective, this underscores the dual role of FASN as both a prognostic indicator and a therapeutic target, suggesting that FASN inhibitors could enhance patient outcomes by diminishing stemness and tumour aggressiveness. These findings pave the way for novel therapeutic strategies for iCCA and shed light on its relationship with metabolic disorders such as diabetes, obesity, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease.
| S-EPMC11486925 | biostudies-literature
Project description:Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.
2025-01-09 | GSE251859 | GEO
Project description:Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.
2025-01-09 | GSE251857 | GEO
Project description:We previously showed that the combination of markers LNGFR+ and THY-1+ can be used selectively to isolate human mesenchymal stem cells (hMSCs) in bone marrow and several tissues. However, the molecular mechanisms regulating stemness of hMSCs remain to be elucidated. In this study, we found that Frizzled 5 (FZD5) and Receptor tyrosine kinase-like orphan receptor 2 (ROR2) were highly enriched in LNGFR+THY-1+ derived clones that retain a high potential for proliferation (rapidly expanding clones; RECs). WNT5A, the ligand of FZD5, causes FZD5 and ROR2 to co-localize and activates non-canonical Wnt pathway in RECs. Moreover, FZD5 knockdown attenuated proliferation and caused senescence. In contrast, FZD5 overexpression delayed senescence. These results indicate that intrinsic activation of non-canonical Wnt signaling via FZD5 and ROR2 modulates stemness and senescence of RECs. Thus, control of non-canonical Wnt signaling would enable us to regulate hMSC quality and to enhance the efficacy of cell-replacement therapy using hMSCs.
2016-09-02 | GSE86369 | GEO
Project description:Macrophage programming rewires cancer‑cell phenotypes
| PRJNA1301792 | ENA
Project description:Porphyrin overdrive rewires cancer cell metabolism
| PRJNA1099386 | ENA