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

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

PROVIDER: PRJNA939709 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23648001_1.fastq.gz	Fastqsanger.gz
	SRR23648001_2.fastq.gz	Fastqsanger.gz
	SRR23648002_1.fastq.gz	Fastqsanger.gz
	SRR23648002_2.fastq.gz	Fastqsanger.gz
	SRR23648003_1.fastq.gz	Fastqsanger.gz

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

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

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 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.

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