Tumor hypoxia and chromatin context as determinants of the outcome of radiotherapy

• Applicant: Dr. Apostolos Menegakis
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 361889788

Among the different types of damage inflicted on the genome by ionizing radiation, DNA double strand breaks (DSBs) pose the most serious threat for the cell. To counteract these detrimental effects, cells have developed a highly sophisticated mechanism to effectively detect and repair these lesions, referred as the DNA Damage response (DDR). Radiation therapy (RT) harness the deleterious effects of DSBs to eradicate malignant cells. However, the efficacy of a RT course is commonly hurdled by the heterogeneity of the tumor microenvironment. Hypoxia is a key feature of tumour microenvironment and it is commonly observed in human tumors. It consist a negative prognostic factor for the outcome of cancer patients and is associated with treatment resistance. Though the latter has been traditionally attributed to the biochemical fixation of DNA damage, it has been increasingly recognized that hypoxic cells can adopt to a more aggressive phenotype through accumulation of alterations in their genome. Such alterations lead to changes in cellular functions, e.g. mutations that potentiate the activation of oncogenes or cause inactivation of tumor suppressor genes. However, in recent years it has become increasingly evident that DNA-sequence-independent, epigenetic alterations occur during malignant progression. It is currently not clear if the altered epigenetic state of a tumor cell is a cause or a consequence of malignant progression, nor is it clear if the changes are cell-intrinsic or induced by the tumor microenvironment. In fact, it is not unlikely that both mechanisms might co-exist. The fact that several chromatin-modifying enzymes have oxygen-dependent regulation and are commonly mutated in human cancers along with the dynamic nature of epigenetic control of gene expression, allowing tumor cells to adapt to microenvironmental changes, has led to intensive research on hypoxia-induced chromatin modifications. However, we currently have limited insights on how changes in chromatin conformation affect the repair of the DSBs. The aim of my research fellowship in the Netherland Cancer Institute (NKI) is to unravel the functional relevance of the local chromatin structure for the efficacy of repair in relation to the cellular oxygenation status. We hypothesize that the efficacy of repair depends on the epigenetic environment in the vicinity of the break site. We aim to gain fundamental understanding of the underlying mechanisms to possibly identify hypoxia-specific epigenetic modifications that are linked to treatment resistance.Understanding how the chromatin context in which a DSB occurs affects the cellular outcome in relation to hypoxia-driven epigenetic changes could offer a powerful tool to recognize recurrent epigenetic modifications that confers treatment resistance. They can be utilized as new biomarkers for therapies stratification and lead to novel targets against hypoxic tumor cells that are a main cause of anti-cancer treatment failure.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Professor Dr. René Medema