Ontology highlight
ABSTRACT:
PROVIDER: PRJNA630293 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11676700_1.fastq.gz | Fastqsanger.gz | |||
| SRR11676700_2.fastq.gz | Fastqsanger.gz | |||
| SRR11676701_1.fastq.gz | Fastqsanger.gz | |||
| SRR11676701_2.fastq.gz | Fastqsanger.gz | |||
| SRR11676702_1.fastq.gz | Fastqsanger.gz |
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Project description:Therapeutic options for patients with relapsed or refractory Ewings sarcoma (EWS) remain limited. Collateral sensitivity, where resistance to one drug confers sensitivity to another, could be leveraged to optimize chemotherapy for EWS. Gene expression signatures that predict collateral sensitivity states can be used to guide treatment selection in an evolution-informed manner. To generate such biomarkers, we experimentally evolved resistance to first-line EWS chemotherapy in independent replicates of an EWS cell line, all originating from the same ancestor population. Throughout, we measured collateral responses across a panel of anticancer drugs and quantified transcriptomic changes. Collateral drug responses varied across replicate evolutionary trajectories, but convergent states of collateral sensitivity emerged across different replicates at different times. By associating these convergent phenotypes with gene expression patterns, we derived a library of predictive signatures for numerous drugs. These signatures accurately distinguished states of collaterally sensitivity from states of collateral resistance within our dataset, irrespective of a replicate's evolutionary history. Our findings demonstrate that gene expression signatures can predict collateral sensitivity in EWS, providing a foundation for personalized therapeutic strategies. This approach also establishes a generalizable workflow for developing predictive biomarkers to guide chemotherapy selection in patients with rare diseases that lack reliable second-line chemotherapy regimens.
2026-03-23 | GSE325674 | GEO
Project description:Chronic Pseudomonas aeruginosa infections evades antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P.aeruginosa towards clinically relevant antibiotics leads to phenotypic convergence towards distinct states. These states are associated with collateral sensitivity towards several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In depth investigation of chronic P.aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.
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Project description:Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity – the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug – has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF -/- cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.
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Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.
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Project description:Fluoroquinolone antibiotics, a common antibiotic for the treatment of Pseudomonas aeruginosa infection, are facing challenges due to the rapid evolution of bacterial resistance. Through designed evolutionary experiments in vitro, we find that there are significant differences in evolutionary trajectories and outcomes of resistant bacteria obtained in different induction modes, among which fitness benefit of resistant strains obtained in high-dose induction mode under high level of antibiotic is significantly higher than that of wild-type strain, and collateral sensitivity to aminoglycosides and some other antibiotics will be obtained. Resistance strains obtained in the low-dose induction mode exhibit higher heterogeneity, which is accompanied by multiple drug resistance (MDR). Through second generation resequencing and proteomic techniques, overexpression of MexCD-OprJ efflux pump induced by mutations in the nfxB gene significantly improved the fitness benefit of Pseudomonas aeruginosa PAO1 under high level of fluoroquinolones. This is the precondition of the further evolution of the fleroxacin-resistant strains in the high dose induction mode, the addition of the efflux pump inhibitor phenylalanyl arginyl β-naphthylamide (PAβN) could effectively repress the evolution of bacterial resistance in the high dose induction mode. Fleroxacin use followed by gentamicin helped drive infectious P.aeruginosa to extinction, causing nfxB mutation to cause collateral sensitivity to gentamicin.
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Project description:Collateral Sensitivity Associated with Antibiotic Resistance Plasmids
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