Collateral Responses to Classical Cytotoxic Chemotherapies are Heterogeneous and Sensitivities are Sparse
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ABSTRACT:
PROVIDER: PRJNA700876 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13665415.fastq.gz | Fastqsanger.gz | |||
| SRR13665416.fastq.gz | Fastqsanger.gz | |||
| SRR13665417.fastq.gz | Fastqsanger.gz | |||
| SRR13665418.fastq.gz | Fastqsanger.gz | |||
| SRR13665419.fastq.gz | Fastqsanger.gz |
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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.
2022-03-23 | GSE166425 | GEO
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:Broad-spectrum multi-target tyrosine kinase inhibitors (mTKIs) are clinically approved for the treatment of soft tissue sarcomas (STS). However, acquired resistance inevitably arises in the majority of STS patients. There is therefore an urgent need to identify new strategies to overcome resistance and achieve durable treatment responses. Here we show that STS cells that acquire resistance to clinically relevant mTKIs are cross-resistant to one another and sequential treatment does not delay the acquisition of drug resistance. Instead, we find that en route to acquiring drug resistance, STS cells develop collateral sensitivities to alternative drugs. We demonstrate that the mTKI sitravatinib rapidly induces collateral sensitivity to the FGFR inhibitor infigratinib which can be exploited for adaptive therapy to suppress STS cell growth. This study provides proof-of-principle that collateral sensitivity may be an effective strategy for overcoming resistance to mTKIs and this novel approach should be explored in the design of future trials.
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Project description:The intrinsic collateral cleavage activity of Cas13d,which refers to the gRNA-independent degradation of bystander RNA, significantly limits its therapeutic potential. To extensively evaluate the collateral effects of hpCas13d genome-wide, we conducted RNA-seq analysis of the transcriptome in HEK293T cells after the transfections with dCas13d, wtCas13d, hpCas13d, and hfCas13d . Compared to dCas13d, wtCas13d with a PPIA gRNA (reported to induce the significant collateral cleavage) resulted in significant downregulations of thousands genes. In sharp contrast, hpCas13d and hfCas13d showed much less off-target genes, respectively. These findings demonstrate that hpCas13d exhibits reduced collateral activity, rendering it suitable for in vivo applications.
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Project description:Genomic analysis of control and collateral arteries was used to investigate mechanisms responsible for impaired collateral growth in the Spontaneously Hypertensive rat, an animal model of essential hypertension with increased oxidative and nitrosative stress and metabolic abnormalities. A fundamental difference was observed in the overall expression pattern in SHR vs WKY collaterals. Redox related genes with altered expression included cyba (the gene encoding p22phox), superoxide dismutase 3, and thioredoxin reductases 1 and 2. Cystatin C, hevin, angiotensinogen, and the angiotensin type 1b receptor (AT1bR) had altered collateral expression that was confirmed by RT-PCR. These molecules are known to have significant roles in other types of arterial remodeling. Of specific interest was the AT1bR which exhibited up-regulation in WKY collaterals, but down-regulation in SHR. A remarkable increase in AT1R protein was observed in WKY but not SHR collaterals. Pharmacological blockade of the AT1R with losartan prevented collateral luminal expansion in WKY. In SHR, captopril restored redox status assessed by cyba expression and nitric oxide concentration, prevented collateral AT1bR down-regulation and re-established the capacity for collateral growth. These results indicate that redox-status significantly alters flow-mediated transcriptional regulation and demonstrate that increased flow-related expression/activation of the AT1R is required for normal collateral luminal expansion but is altered by chronic oxidative and/or nitrosative stress in hypertensive rats. Keywords: gene expression two strains: two vessel types
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Project description:LbuCas13a exhibits widespread collateral RNA cleavage in human cells after activation by a specific target RNA. We wanted to explore the cells response to this collateral RNA cleavage. Therefore we performed RNA-seq at 16 hours after RNP transduction. From prior experiments we know that at this timepoint RNA integrity has largely recovered and cells are entering apoptosis.
2023-01-19 | GSE220759 | GEO
Project description:Collateral fitness effects of mutations
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Project description:The CRISPR/Cas13 system has garnered attention as a potential tool for RNA editing. However, the degree of collateral activity among various Cas13 orthologs and their cytotoxic effects in mammalian cells remain contentious, potentially impacting their applications. In this study, we observed differential collateral activities for LwaCas13a and RfxCas13d in 293T and U87 cells by applying both sensitive dual-fluorescence (mRuby/GFP) reporter and quantifiable dual-luciferase (Fluc/Rluc) reporter, with LwaCas13a displaying notable activity contrary to previous reports. However, significant collateral RNA cleavage exerted only a modest impact on cell viability. Furthermore, the collateral activity of LwaCas13a mildly impeded but did not arrest, porcine embryo development. Our findings reveal that distinct collateral RNA cleavage by Cas13 slightly suppresses mammalian cell proliferation and embryo development. This could account for the lack of reported collateral effects in numerous prior studies and offers new insights into the implications of the collateral activity of Cas13 for clinical application.
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Project description:using peripheral blood monocytes to identify marker genes for an extensively grown coronary collateral circulation. We used microarrays to detail the global programme of gene expression underlying collateralization and identified distinct classes of differently regulated genes during this process. Experiment Overall Design: Collateral flow index (CFI) was obtained invasively by angioplasty pressure sensor guidewire, a group of patients with coronary artery disease CAD and a group without CAD were selected for peripheral monocyte isolation, RNA extraction and hybridization on Affymetrix microarrays.
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