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Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

ABSTRACT: Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

PROVIDER: PRJNA927037 | ENA |

REPOSITORIES: ENA

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Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

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

RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

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

RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

Project description:RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

| PRJNA860213 | ENA

Fractionated irradiation of breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype

Project description:Fractionated irradiation of breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype

| PRJNA783278 | ENA

Non-canonical Wnt signaling via FZD5 and ROR2 contributes to the maintenance of the stemness of human mesenchymal stem cells

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

Porphyrin overdrive rewires cancer cell metabolism

Project description:Porphyrin overdrive rewires cancer cell metabolism

| PRJNA1099386 | ENA

MEC coupling AD-1

Project description:MEC coupling AD-1 Raw sequence reads

| PRJNA482710 | ENA

c-Met regulation of tumor initiation and stemness occurs through CD44s

Project description:c-Met induces tumor initiation and stemness in HCC cells through the regulation of CD44s via AKT signaling. Over-expression of CD44s in c-Met and CD44s negative cells induce both a stemness and mesenchymal phenotype independent of c-Met. The down regulation of CD44s or c-Met was compared to Scrambled control to investigate the effects of CD44s or c-Met on global changes of mesenchymal or stemness markers.

2012-05-30 | E-GEOD-38343 | biostudies-arrayexpress

Characterisation of the stemness of human thyroid organoids by transcriptome profiling.

Project description:The stemness of primary thyroid samples in comparison to early and late passages of organoids was characterised by whole transcriptome analysis in addition to focussed analysus of published stemness markers.

2021-01-19 | E-MTAB-6274 | biostudies-arrayexpress

ATF6 promotes colorectal cancer growth and stemness by regulating the Wnt pathway

Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt UPR signaling by IRE1 and PERK to sustain tumor growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference also disabled Myc and Wnt signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, reducing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism rescued the growth inhibitory phenotype of ATF6 interference. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC.

2024-08-12 | MSV000095581 | MassIVE

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