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Investigating therapy-induced senescence as a reversible escape mechanism of drug resistance in breast cancer cells using high-dose doxorubicin treatment [RNA-seq]

ABSTRACT: The emergence of drug resistance remains a critical challenge in cancer treatment, significantly contributing to high mortality rates. Here, we investigate therapy-induced senescence (TIS) as a reversible escape mechanism of drug resistance in breast cancer cells. Using high-dose doxorubicin, we induced TIS in MCF7, T47D, MDA-MB-231 and Hs578T breast cancer cell lines. Bulk RNA sequencing revealed a unique transcriptomic profile in TIS cells, distinct from both parental and repopulated cells in every cell line, exposing a small subpopulation of TIS cells with the potential to escape senescence. Gene set enrichment analysis indicated significant downregulation of proliferation-related genes, downregulation of DNA repair pathways, and the upregulation of immune response related genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287953 | GEO | 2025/05/07

REPOSITORIES: GEO

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Project description:The purpose of this study was to determine whether leukemia cells can escape from drug-induced senescence; determine the phenotype of the senescent, and escaped cells, and whether senescent leukemia cells can be specifically eliminated prior to their escape. Methods: DA3/EPOR cells were treated with 200ng/ml doxorubicin for 24 hr. Cells were confirmed to enter and exit senescence based on, proliferating and SA-gal staining. mRNA transcriptional profiles of naïve proliferating, senescent, and escaped DA3/EPOR murine leukemia cells were generated by deep sequencing, in biological triplicate, using Illumina NovaSeq 6000 at a depth of 25 million pair-ended reads that were 100 bp in length. The sequence reads that passed quality filters, the first 13 nucleotides were removed from each read. Alignment to the MM10 indexed genome was done using HiSAT2. Read counts were genereated using HTSEQ, which were then used for differential expression. Differential expression was performed on Rstudio using EdgeR. qRT–PCR was performed for validation. Results: We report that DA3/EPOR leukemia cells enter and escape a doxorubicin (Dox)-induced senescence, dependent on erythropoietin (EPO). EPO is necessary for DA3/EPOR cells to survive the senescent state. Senescent DA3/EPOR cells undergo a transcriptional reprogramming, which is largely reversible upon escape. Escaped DA3/EPOR cells mirror naïve, never senescent DA3/EPOR cell, and respond similarly to Dox. Senescent DA3/EPOR cells mimic a diapause-like state, and undergo metabolic changes. Senescent DA3/EPOR cells and some drug-induced senescent human acute myeloid leukemia (AML) cells can be eliminated with chloroquine, a lysosome inhibitor. Lastly, we show with The Cancer Genome Atlas publicly available data that the senescent signature is associated with decreased survival in AML and multiple other cancers. Conclusion: Leukemia cells persist through drug treatment by entering a reversible senescent state that mimics diapause. Senescent leukemia cells depend on lysosome activity to persist, and treatment with chloroquine, a lysosome inhibitor, can eliminate senescent leukemia cells.

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Investigating therapy-induced senescence as a reversible escape mechanism of drug resistance in breast cancer cells using high-dose doxorubicin treatment [RNA-seq]

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