Project: Mechanisms promoting cellular transformation and resistance to chemotherapy
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
Master’s degree in biological sciences
Strong interest in molecular/cell or cancer biology
Good communication skills and the ability to work in a team
Prior experience with NGS, bioinformatics or metabolism will be considered an advantage
Burocziova M, Danek P, Oravetzova A, Chalupova Z, Alberich-Jorda M, Macurek L: Ppm1d truncating mutations promote the development of genotoxic stress-induced AML. Leukemia 202337(11):2209-2220. [pubmed] [doi]
Fons NR, Sundaram RK, Breuer GA, Peng S, McLean RL, Kalathil AN, Schmidt MS, Carvalho DM, Mackay A, Jones C, Carcaboso ÁM, Nazarian J, Berens ME, Brenner C, Bindra RS. PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nat Commun. 201910(1):3790. [pubmed] [doi]
Zhang L, Hsu JI, Braekeleer ED, Chen CW, Patel TD, Martell AG, Guzman AG, Wohlan K, Waldvogel SM, Uryu H, Tovy A, Callen E, Murdaugh RL, Richard R, Jansen S, Vissers L, de Vries BBA, Nussenzweig A, Huang S, Coarfa C, Anastas J, Takahashi K, Vassiliou G, Goodell MA. SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells. Elife. 202412:RP91611. [pubmed] [doi]
