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Analysis of chemotherapy-induced cellular plasticity of DTPs in triple negative breast cancer
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International audience. Tumor resistance has long been considered exclusively from a deterministic perspective, as the result of a Darwinian selection of a rare pre-existing or de novo generated population with genetic mutations that promote resistance and tumor growth. However, some studies point to the existence of a cellular subpopulation capable of tolerating the treatment independently of genetic mutations. A model of resistance is emerging with the phenotype definition of "Drug Tolerant Persisters" (DTP) whose ability to regenerate a tumor, following chemotherapy.A complete characterization of mechanisms leading to DTP formation is essential to identify vulnerabilities to be exploited for future treatment strategies aimed at eliminating DTPs or preventing their revival and disease recurrence. In order to study DTPs, we established a DTP model in response to gemcitabine characterized by a drastic cell population elimination, and by a quiescence period of at least a week following the therapy cessation, followed by proliferation resumption.My thesis will allow us to thoroughly characterize the transcriptional mechanisms underlying the phenotypic switches associated with entry and exit of the persistent phenotype. This project begins with the characterization using temporal scRNA-Seq of the transcriptional changes that initiate the conversion of cancer cells to DTP, as well as the changes that promote DTP cell exit and growth resumption. These results will allow us to identify key regulators of these programs, then so, using reporter cell lines, study their expression level, in collaboration with Dr. Anquez, in single cells by time lapse microscopy. The next step will be to validate targets and compare our results with clinical data in breast cancer patients.My project will provide an in-depth characterization of the transcriptional mechanisms underlying the phenotypic switches associated with entry and exit of the persistent phenotype, in order to identify vulnerabilities.
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