Institute of Molecular Genetics of the Czech Academy of Sciences
Supervisor
Libor Macůrek
Project description
Genome instability is one of the drivers of cellular transformation and cancer development. Tumor suppressor p53 prevents proliferation of cells with damaged DNA and eliminates them either by programmed cell death or by induction of a permanent cell cycle arrest. We have recently shown that increased activity of protein phosphatase PPM1D promotes development of breast cancer and/or hematological malignancies by inhibiting p53 pathway. Interestingly, suppression of the cell cycle checkpoint may not be the only pathogenic mechanism supporting the transformation of cells lacking p53 or overexpressing PPM1D. In this project, we will investigate defects in signaling pathways in cells that transformed due to the presence of the pathogenic variant of PPM1D. In particular, we will focus on mechanisms that are not directly linked with the cell cycle control and instead are involved in cellular metabolism. PPM1D activity can also contribute to resistance of cancer cells to chemotherapy. We will therefore exploit CRISPR/Cas9 screens to identify potential synthetic lethal interactions with the pathogenic variants of PPM1D. Selected hits will be validated using xenograft mouse models. This project will identify new vulnerabilities of cancer cells expressing active PPM1D and can potentially define novel chemotherapeutic combinations.
Candidate profile
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