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Cycling cancer persisters arise from lineages with distinct transcriptional and metabolic programs

ABSTRACT: Cycling cancer persisters arise from lineages with distinct transcriptional and metabolic programs

PROVIDER: PRJNA634136 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11819902.fastq.gz	Fastqsanger.gz
	SRR11819903.fastq.gz	Fastqsanger.gz
	SRR11819904.fastq.gz	Fastqsanger.gz
	SRR11819905.fastq.gz	Fastqsanger.gz
	SRR11819906.fastq.gz	Fastqsanger.gz

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Cycling cancer persisters arise from lineages with distinct transcriptional and metabolic programs

Project description:Non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment. While most cancer persisters, like their bacterial counterparts, remain arrested in the presence of drug, a rare subset of cancer persisters can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to simultaneously resist therapy and maintain proliferative capacity in the presence of drug. To address this, we developed Watermelon, a new high-complexity expressed barcode lentiviral library for simultaneous tracing each cell's clonal origin, proliferative state, and transcriptional state, and used it to study this rare, transiently-resistant, proliferative persister population and identify what distinguishes it from non-cycling persisters. Analysis of Watermelon-transduced cancer cell lines demonstrated that cycling and non-cycling persisters arise from different pre-existing cell lineages with distinct transcriptional and metabolic programs. The proliferative capacity of persisters is associated with an upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation in specific subpopulations of tumor cells.

2020-05-21 | GSE150949 | GEO

Salmonella persisters undermine host immune defences during antibiotic treatment

Project description:Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters that are considered dormant cells when bacteria are grown in laboratory medium. Non-growing persisters also form following uptake of Salmonella by macrophages but their nature is little understood. Here we show that Salmonella persisters arising during macrophage infection maintain an active state. Persisters reprogram macrophages by means of effectors secreted by the SPI-2 Type 3 Secretion System (T3SS), thereby dampening pro-inflammatory innate immune responses and inducing anti-inflammatory macrophage polarisation. Reprogramming allows non-growing Salmonella to survive for extended periods in their host. Persisters undermining the host immune defences might confer an advantage to the pathogen during relapse once the antibiotic pressure is relieved.

2018-12-07 | GSE104785 | GEO

Intracellular Staphylococcus aureus persisters upon antibiotic exposure

Project description:Bacterial persister cells are phenotypic variants that exhibit a transient non-growing state and antibiotic tolerance. Here we provide in vitro evidence of Staphylococcus aureus persisters within infected host cells. We show that the bacteria surviving antibiotic treatment within host cells are persisters, displaying biphasic killing and reaching a uniformly non-responsive, non-dividing state when followed at the single-cell level. This phenotype is stable but reversible upon antibiotic removal. Intracellular S. aureus persisters remain metabolically active, but display an altered transcriptomic profile consistent with activation of stress responses, including the stringent response as well as cell-wall stress, SOS and heat-shock responses. These changes are associated with multidrug tolerance after exposure to a single antibiotic. We hypothesize that intracellular S. aureus persisters may constitute a reservoir for relapsing infection, and could contribute to therapeutic failures.

2020-03-25 | GSE139659 | GEO

Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages

Project description:Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages

| PRJNA727557 | ENA

Definition of germ cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

Project description:Alternative splicing is critical for development. However, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-specific RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes likely arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Collectively, our results thus uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.

2022-02-01 | MSV000088762 | MassIVE

Proteomics Analysis of Escherichia coli Persisters

Project description:Persisters, a dormant and multi-drug tolerant subpopulation that are able to resuscitate after antibiotic treatment, have recently received considerable attentions as the major risk of the relapse of various infectious diseases in clinics. However, due to their low abundance and inherent mutability, it is extremely difficult to study them by proteomics. Here, we developed a magnetic beads-based separation approach to enrich Escherichia coli persisters and then subject them to Filter-Aided Sample Perparation (FASP) followed by LC-MS/MS analysis. We applied spectral counting-based quantitative proteomics to study the proteomic changes of E. coli persisters under high concentration of ampicillin treatment.

2018-10-16 | PXD010590 | Pride

Host cholesterol modulates the generation and enrichment of persisters during Mycobacterium tuberculosis infection

Project description:A worldwide increase in the frequency of multidrug-resistant and extensively-drug-resistant cases of tuberculosis is mainly due to the therapeutic noncompliance associated with a lengthy treatment regimen. This protracted regimen is attributed to a supposedly nonreplicating and metabolically inert subset of the Mycobacterium tuberculosis (Mtb) population, called ‘persisters’. We have earlier reported that the utilization of host cholesterol is essential for Mtb persistence. However, the mechanism underlying stochastic generation and enrichment of persisters is not fully known. In this study, we showed that cholesterol-induced activation of ribonuclease toxin (VapC12) inhibits translation by targeting proT tRNA and is critical for the generation of persisters in a heterogeneous Mtb population. A vapC12-null mutant strain (ΔvapC12) failed to persist and showed hypervirulence in a guinea pig model of tuberculosis. We identify a novel strategy through which cholesterol-specific activation of a toxin–antitoxin (TA) module in Mtb leads to the persister formation during infection. Our study provides an opportunity for targeting persisters, a new paradigm facilitating tuberculosis drug development.

2020-11-05 | GSE135952 | GEO

Drug tolerant persisters in erlotinib treated EGFR-mutated lung adenocarcinoma arise from pre-existing tumor cells and survive in an adapted stromal microenvironment

Project description:Drug tolerant persisters in erlotinib treated EGFR-mutated lung adenocarcinoma arise from pre-existing tumor cells and survive in an adapted stromal microenvironment

| PRJNA816436 | ENA

Explore the gene expression files of HGECs after P. gingivalis persisters treatment via RNA sequencing

Project description:This study investigated how P. gingivalis persisters interacted with human gingival epithelial cells (HGECs) and affected the gene expression of cytokines, and the related signaling pathways, via RNA sequencing. P. gingivalis (ATCC 33277) was treated with metronidazole (100 μg/ml) for 6 hours to generate P. gingivalis persisters (M-PgPs). HGECs with or without IL-1β pretreatment were stimulated by M-PgPs and P. gingivalis for 24 hours, and those without any treatments served as the blank control (BL).

2022-05-31 | GSE184777 | GEO

Transcriptome analysis of Streptococcus mutans quorum sensing-mediated persisters reveals an enrichment in genes related to stress-defense mechanisms

Project description:Persisters are a small fraction of growth-arrested phenotypic variants that can survive lethal concentrations of antibiotics but are able to resume growth once antibiotics are stopped. Their formation can be a stochastic process or triggered by environmental cues. In the human pathogen Streptococcus mutans, the canonical peptide-based quorum sensing system is an inducible DNA repair system that is pivotal for bacterial survival. Previous work showed that the CSP signaling peptide is a stress-signaling alarmone that promotes the formation of stress-induced persisters. In this study, we exposed S. mutans to the CSP pheromone to mimic DNA damage conditions and isolated the antibiotic persisters by treating the cultures with ofloxacin. Transcriptome analysis was then performed to evaluate the differential gene expression between the normal stationary phase cells and the persisters. RNA-sequencing revealed that triggered persistence was associated with the up-regulation of genes related to several stress-defense mechanisms, notably, multidrug efflux pumps, the arginine deaminase pathway, and the Opu/Opc system. In addition, we showed that inactivation of the VicK kinase of the YycFG essential two-component regulatory system abolished the formation of triggered persisters via the CSP pheromone. These data contribute to the understanding of the triggered persistence phenotype and may suggest new therapeutic strategies for treating persistent streptococcal infections

2023-09-29 | GSE244067 | GEO

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