Exploiting evolutionary steering to induce collateral drug sensitivity in cancer
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ABSTRACT:
PROVIDER: PRJEB37838 | ENA |
REPOSITORIES: ENA
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Project description:This study contains single cell RNA-seq of the non-small cell lung cancer line HCC827 in three conditions. Firstly we have sequenced the RNA of single cells of a culture of HCC827 cells grown in normal conditions (POT). In our study we then evolved two arms of the cell line, one in the presence of the drug gefitinib (40nM, G1) and the other in the presence of trametinib (100nM, T4) in HYPERflasks to avoid replating. These data were analysed using cellRanger using GRCh38. Output from cellRanger was filtered for a minimum number of detected genes and UMIs. Mitochondrial reads were excluded from analysis (Acar_2020_single_cell_raw_data.txt). The data was then imported and scaled using the package Seurat. Scaled data was then filtered for low expression of housekeeping genes. Additionally genes expressed in fewer than 20 cells were excluded from analysis. Data was then renormalised using linear normalisation and scaling on the filtered raw data (Acar_2020_single_cell_processed_data.txt). Principal component analysis was run on variable genes identified using Seurat and the top 44 component were used as input for t-SNE analysis. Clusters were then identified using FindClusters in Seurat (Acar_2020_single_cell_metadata.txt). For a full description see the associated publication.
2020-08-18 | E-MTAB-8809 | biostudies-arrayexpress
Project description:Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.
| S-EPMC7174377 | biostudies-literature
Project description:The rise of antibiotic resistance and decline of antibiotic discovery urgently calls for novel mechanistic understanding of pharmacological and evolutionary interactions between antibiotics and multidrug resistant bacteria to revitalize existing antibiotics. The evolutionary cross-resistance to antibiotics has received intensive attention previously. Nevertheless, whether and how bacteria develop negative responses, under the selective pressure of antibiotics by inverting the evolutionary trajectory remains unclear. Here we found an instance of collateral sensitivity, in which clinical vancomycin-resistant Enterococcus faecium (VREfm) pathogens exhibit dramatic and specific susceptibility to pleuromutilin antibiotics, decreased minimal inhibitory concentrations (MICs) from 128 µg/mL to 0.03 µg/mL. The unique trade-off between vancomycin and pleuromutilins is mediated by the epistasis between the van gene cluster and msrC encoding an ABC-F protein protecting bacterial ribosomes. We validated the efficacy of pleuromutilins in vivo through reducing colonization and promoting microbiota restoration. Our findings provide an alternative approach to inverting the selective advantage and reversing the route of vancomycin resistance evolution, and to treat VREfm associated infections.
2022-05-20 | PXD030906 | Pride
Project description:Phenotypic convergence in response to drug exposure supports exploitation of collateral sensitivity to counter drug resistance
| PRJEB22929 | ENA
Project description:In this study, using a murine model of Ph+ acute lymphoblastic leukemia (Ph+ ALL), a combined pharmacological profile and drug selection experimental approach identified distinct stages of tumor clonal evolution with vulnerabilities to sets of small molecules. Through genotypic, phenotypic, signaling, and binding measurements, we identified the mutation V299L in the ABL1 kinase domain as mediator for an on-target ABL1 inhibition and hence the sensitization phenotype. To further rule out any off-target effects, we performed RNA-seq analysis of select derived cell lines. Variant calls suggest that although there were other mutations, the only mutation shared among cell lines with the sensitization phenotype and that went from 0% to 100% variant allele frequency was c.895G>C, leading to BCR-ABL1 V299L. In addition, transcriptional profile does not suggest functional changes in BCR-ABL1 V299L and WT cell lines. RNA-seq of parental murine Ph+ acute lymphoblastic leukemia (Ph+ ALL) cell line and derived cell lines (via dose escalating concentrations of dasatinib or DMSO vehicle control).
2016-04-05 | E-GEOD-72910 | biostudies-arrayexpress
Project description:Drug resistance, mediated by intra-tumour heterogeneity and clonal evolution, is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at the cost of increased sensitivity to another due to so-called evolutionary trade-offs. This weakness can be exploited in the clinic using an approach called ‘evolutionary herding’ that aims at controlling the tumour cell population to delay or prevent resistance. However, model systems able to recapitulate cancer evolution experimentally are lacking and current in vitro techniques based on small populations, re-plating and escalating dose, are unsuitable to develop evolutionary herding strategies. We present a novel methodology for evolutionary herding in vitro and ex vivo using patient-derived organoids. Our approach is based on a combination of single-cell barcoding, very large populations of 108-109 cells grown without re-plating, realistic high drug doses, time-course monitoring of cancer clones, and mathematical modelling of tumour evolutionary dynamics. We demonstrate evolutionary herding in non-small cell lung cancer in vitro and in patient-derived colorectal cancer organoids (PDO). We show that herding causes controlled evolutionary bottlenecks that lead to collateral sensitivity. Through genomic analysis, we were also able to determine the mechanisms that drive such sensitivity. Our approach allows modelling evolutionary trade-offs experimentally to test patient-specific evolutionary herding strategies that can be translated into the clinic to control treatment resistance.
| EGAS00001003200 | EGA
Project description:In this study, using a murine model of Ph+ acute lymphoblastic leukemia (Ph+ ALL), a combined pharmacological profile and drug selection experimental approach identified distinct stages of tumor clonal evolution with vulnerabilities to sets of small molecules. Through genotypic, phenotypic, signaling, and binding measurements, we identified the mutation V299L in the ABL1 kinase domain as mediator for an on-target ABL1 inhibition and hence the sensitization phenotype. To further rule out any off-target effects, we performed RNA-seq analysis of select derived cell lines. Variant calls suggest that although there were other mutations, the only mutation shared among cell lines with the sensitization phenotype and that went from 0% to 100% variant allele frequency was c.895G>C, leading to BCR-ABL1 V299L. In addition, transcriptional profile does not suggest functional changes in BCR-ABL1 V299L and WT cell lines.
2016-04-05 | GSE72910 | GEO
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.
2024-02-28 | GSE260500 | GEO
Project description:The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph(+) acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.
| S-EPMC5152932 | biostudies-literature