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Elucidating and Pharmacologically Targeting Master Regulators of Stem-like Breast Cancer Cell State

ABSTRACT: In many tumors, small subpopulations of stem-like cells can exist in drug-resistant states that are transient and epigenetically governed. Single-cell RNA sequencing provides transcriptional profiles for individual cells which, although sparse and noisy, may provide insight into how they are regulated and how they may be targeted. We took a systems-biology approach to analyzing stem-like cells in breast tumors and predicting how this drug-resistant subpopulation might be sensitized to treatment. Our analysis predicted that the anthelmintic albendazole would reprogram the stem-like population, and a subsequent sensitizing-then-kill experiment in triple negative breast cancer PDX mice revealed a synergistic relationship between albendazole and the first-line treatment, paclitaxel. These results are a proof of concept that it is possible to use, a systems biology approach to identify drugs that can reprogram cell-state, and that tumor subpopulations which have long been considered intractable may be forced into a sensitive state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226329 | GEO | 2024/06/05

REPOSITORIES: GEO

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Elucidating and Pharmacologically Targeting Master Regulators of Stem-like Breast Cancer Cell State (CROP-Seq)

Project description:In many tumors, small subpopulations of stem-like cells can exist in drug-resistant states that are transient and epigenetically governed. Single-cell RNA sequencing (scRNA-seq) provides transcriptional profiles for individual cells which, although sparse and noisy, may provide insight into how they are regulated and how they may be targeted. We took a systems-biology approach to analyzing cancer stem-like cells (CSLCs) in breast tumors and predicting Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing drug sensitivities that may be leveraged via combination therapy. The MRs were validated by pooled, CRISPR-KO mediated CROP-seq profiling of single cells representing either the CLSC or the differentiated breast cancer (BRCA) cells.

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Expression data from Caenorhabditis elegans exposed to albendazole

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Expression data from Caenorhabditis elegans exposed to albendazole

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AtacWorks: A deep convolutional neural network toolkit for epigenomics

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Holistic engineering of cell-free systems through proteome-reprogramming synthetic circuits

Project description:Synthetic biology has focused on engineering genetic modules that operate orthogonally from the host cells. A synthetic circuit, however, can be designed to reprogram the host proteome, which in turn enhances the function of the synthetic circuit. Here, we apply this holistic synthetic biology concept by exploiting the crosstalk between metabolic networks in cells, leading to a protein environment more favorable for protein synthesis. Specifically, we show that a local module expressing translation machinery can reprogram the bacterial proteome, changing the expression levels of more than 780 proteins. The integration of the proteins synthesized by the local modules and the reprogramed proteome generate a cell-free system that can synthesize a diverse set of proteins in different reaction formats, with up to 5-fold higher expression level than classical cell-free systems. Our work demonstrates a holistic approach that integrates synthetic and systems biology concepts. This approach has the potential to achieve outcomes not possible by only local, orthogonal circuits.

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Systems biology of prostate cancer

Project description:Systems biology of prostate cancer

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Project description:Anthelmintic resistance is a major problem in the global fight against parasitic nematodes., Most previous studies have focused on the analysis of potential candidate genes that may have a role in resistance. Here we take a novel approach in the important parasite, Haemonchus contortus, by investigating changes in microRNA expression between resistant and susceptible parasites. The resistant worms included two geographically distinct strains and two lines generated by multiple rounds of backcrossing between susceptible and resistant parents, with ivermectin selection. All four resistant strains showed increased abundance of a single miRNA, hco-miR-9551, compared to the susceptible strain. hco-miR-9551 is enriched in female worms, is likely to be located on the X chromosome and is found only in clade V parasitic nematodes. Approximately 5-10% of the genomes of the resistant parental strains are introgressed into the respective backcrosses, suggesting that hco-miR-9551, or genes regulated by the miRNA, may be genetically linked to a locus that determines resistance. Genes containing predicted binding sites for hco-miR-9551 were identified computationally and refined based on differential expression in a transcriptomic dataset. These findings advance our conceptual understanding of the molecular mechanisms of anthelmintic resistance in H. contortus and indicate that altered miRNA expression may be linked with drug resistance. All samples were carried out using three biological replicates

2016-03-25 | E-GEOD-79542 | biostudies-arrayexpress

Transcriptional profiling of DNA damage tolerant (DDT) lymphomas after treatment either with Albendazole, Ethidium bromide or DMSO as a control

Project description:We studied the role of Albendazole in inducing loss of heterozygosity. Here, we generated RNA-seq data from DDT lymphomas after 12 hours of treatment either with Albendazole (400nM), Ethidium bromode (400 nM) or DMSO as a control.

2021-02-05 | GSE163419 | GEO

Application of a 9k-cDNA microarray for identification of albendazole and artemisinin targeting genes in Echinococcus granulosus larval protoscoleces

Project description:A cDNA microarray composed of 9065 uniEST probes was constructed and applied to detect the gene expression profile of protoscoleces of E. granulosus treated with albendazole and artemisinin in vitro, respectively. Compared with the untreated parasite, 7 genes were up-regulated and 38 genes were down-regulated in protoscoleces treated with albendazole and 100 genes were up-regulated and 6 genes were down-regulated in protoscoleces treated with artemisinin. The differential expression genes in protoscoleces induced by albendazole were clustered into energy metabolism, cell cycle and assembly of cell structure. And the differential expression genes affected by artemisinin were clustered into genetic information, the transduction of environmental signals, metabolism. Under transmission electron microscope observation, albendazole intervention damaged the cell structure, and form the heterochromatin in protoscoleces cells was mainly increased in the artemisinin group. Isolated E. granulosus protoscoleces were treated with albendazole and artemisinin respectively and was extracted of total RNA using the TRIZOL Reagent according to the manufacturer's instructions. Gene-expression profiling was performed for each RNA sample separately on the GeneChip of Echinococcus granulosus Genome Array (Capitalbio) at CapitalBio Corporation (Beijing, China).

2014-06-03 | E-GEOD-58136 | biostudies-arrayexpress

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