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Determining how microenvironments affect tumour progression and radiation responses.

Mouse tumour tissue (4T1 cells xenograft model) stained with markers for hypoxia (EF5), angiogenesis (CD31), and perfusion (Hoechst 33342) shows heterogeneity of tumour microenvrionment

SUMMARY:

Our research focuses on determining how microenvironments affect tumour progression and radiation responses. We are specifically interested in MAFF, a bZIP transcription factor, which plays a significant role in antioxidant responses. While RT induces cell killing by direct DNA damage, approximately two-thirds of radiation damage is induced indirectly through increased production of reactive oxygen species (ROS). In addition to their role in DNA damage, ROS regulate signal transduction and redox pathways to promote tumour cell survival and expansion (1). To increase the efficacy of RT in killing tumour cells, we need to manipulate the redox environment of cancer cells focusing on ROS-sensing signalling pathways.

MAFF, which lacks a transactivation domain, is an essential binding partner of well-known regulators of antioxidant responses such as NRF2 and BACH1 (2). In our recent study, we demonstrated that MAFF promotes tumour cell invasion and metastasis both in vitro and in vivo using breast cancer models. Through RNA- and ChIP-sequencing, we identified IL11 as a direct transcriptional target of MAFF that mediates the invasive and metastatic behaviour of tumour cells. Since breast cancers express low levels of NRF2, which is a well-known binding partner of MAFF that regulates cellular antioxidant responses, we used mass spectrometry to determine MAFF binding partners and found that BACH1 was the most abundant MAFF binding partner of MAFF in our breast cancer models. Expanding this study to ovarian and lung cancer models, we also confirmed that MAFF enhances tumour invasion and metastasis, indicating its important role in a variety of tumour types. This work has been accepted for publication in Nature Communications (2021, In Press).

Figure 1. In breast cancer patient tissues, MAFF expression (brown staining) is detected, and its intensity increases in more metastatic and aggressive tumours.

We will further expand our studies to evaluate the role of MAFF in tumour metabolism and redox pathways in response to radiation. Specifically, we aim to investigate the role of MAFF in ferroptosis, a non-apoptotic cell death depending on iron and lipid peroxides that can contribute to radiation-induced cell death (3, 4, 5). Since MAFF acts as a transcriptional activator and a repressor, we will demonstrate how MAFF regulates ferroptosis depending on tumour microenvironments.

Our main aims are 1) to determine how MAFF regulate ferroptosis through redox pathways and metabolism, 2) to examine how MAFF transcriptionally activate or repress target genes in response to hypoxia and radiation, and 3) to investigate whether MAFF-mediated redox changes can be beneficial to FLASH treatment, a novel ultra-high dose rate radiotherapy (6). By focusing on FLASH radiotherapy and MAFF-mediated cell death pathways, we will provide a new insight in how transcriptional regulation leads to physiological changes in tumour, which might affect treatment outcomes. 

IMPACT:

Our programme will determine how MAFF regulates ferroptosis by altering its target genes and consequently, redox responses and lipid metabolism. While ferroptosis has been identified as a novel pathway of radiation-induced cell death, the key regulator of this pathway still needs to be determined. Our preliminary data found a significant link between MAFF and ferroptosis. Given that targeting MAFF is pharmacologically challenging, as it is a nuclear transcription factor, we will focus on identifying MAFF target genes or metabolites to develop novel strategies to increase tumour response to current radiation treatment. In addition, we will examine the effect of FLASH, a new form of radiotherapy, on ferroptosis to determine whether MAFF-mediated redox pathways play a role in response to FLASH treatment.

REFERENCES:

1. Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr Biol 24, R453-462, doi:10.1016/j.cub.2014.03.034 (2014)

2. Moon, E. J. & Giaccia, A. Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radic Biol Med 79, 292-299, doi:10.1016/j.freeradbiomed.2014.11.009 (2015)

3. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060-1072, doi:10.1016/j.cell.2012.03.042 (2012).

4. Lang, X. et al. Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11. Cancer Discov 9, 1673-1685, doi:10.1158/2159-8290.CD-19-0338 (2019).

5. Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 30, 146-162, doi:10.1038/s41422-019-0263-3 (2020).

6. Wilson, J. D., Hammond, E. M., Higgins, G. S. & Petersson, K. Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold? Front Oncol 9, 1563, doi:10.3389/fonc.2019.01563 (2019).