The crosstalk between tumour microenvironments and MAFF to determine transcriptional activation or repression
About the research:
Radiation is effective in treating many types of cancers by inducing oxidative stress through the generation of reactive oxygen species (ROS) that result in DNA damage, in particular, DNA double strand breaks (DSBs). However, both tumour intrinsic mechanisms for suppressing ROS as well as the hypoxic microenvironment reduce the efficacy of RT. While significant efforts are being pursued to target the DNA damage response (DDR) to enhance radiation efficacy, we will focus on RT-induced ROS that kill cells by inducing ferroptosis through a hypothetically DNA damage independent mechanism. Ferroptosis has recently been described as a non-apoptotic form of cell death dependent on iron and lipid peroxides that contributes to radiation-induced cell death. Studies suggest that the ferroptosis pathway is independent of DSBs and that enhancing ROS induced lipid peroxidation can promote cell killing as well as overcome the problem of tumour radioresistance mediated by intrinsic radical scavengers. However, before developing strategies to clinically translate the radiosensitisation of tumour cells through RT-induced ferroptosis, it is critical to determine the signals and key genetic pathways in the regulation of ferroptosis in response to radiation. We propose to explore the effectiveness of different types of radiation, which induce different levels of ROS, on ferroptosis induction. This will entail looking at how both intrinsic as well as extrinsic ROS inhibitory pathways affect RT-induced ferroptosis.
Recently, we found that V-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) plays a significant role in ferroptosis by modulating ROS production and lipid metabolism. Therefore, we will determine the role of MAFF and its transcriptional target for RT-induced ferroptosis to gain insight into potential mechanisms of resistance. By doing so, we will add scientific values of possible therapeutic regimen to enhance radiosensitisation and diagnostic markers to predict radiation outcome.
To determine molecular pathways in radiation-induced ferroptosis, we will work using basic science to preclinical science techniques. Specifically, by focusing on tumour metabolism, we will identify key metabolites that can be targeted or be used as a diagnostic marker. The student will be trained to perform basic cell and molecular biology as well as mouse and patient sample research including chromatin immunoprecipitation, immunohistochemistry, and patient-derived organoid culture. In addition, through weekly departmental seminars, journal clubs, and manuscript review, skills for presentation, data management, and scientific writing will be trained.
Moon EJ et al. (2021). The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature Communications. 12, 4308. https://doi.org/10.1038/s41467-021-24631-6.