DISCOVER: Project investigates the influence of radiation on the formation of brain tumours

Background

DISCOVER is a multidisciplinary research project that examines how low doses of ionising (i.e. high-energy) radiation affect the development of brain tumours. Radiation-induced carcinogenesis has traditionally been attributed to unrepaired or incorrectly repaired DNA damage. However, recent evidence suggests that the microenvironment of the brain and epigenetic changes play crucial roles in tumour formation. In order to develop more effective radiation protection strategies, it is essential to better understand these processes and the interplay of mechanisms in radiation-induced cancers. These new findings are particularly valuable for enhancing radiation protection in occupational and medical settings in which people are exposed to radiation.

Objective

The aim of DISCOVER is to provide comprehensive insights into how radiation influences brain tumour formation using medulloblastoma as a model. The project examines both direct effects on target cells and the influence of the microenvironment. To achieve this, the project focuses on the following sub-objectives:

• Identification of molecular changes at the DNA, RNA, and protein level in brain tissue after in vivo radiation in a mouse model
• Clarification of cell communication processes between tumour-initiating cells and the microenvironment through investigations in ex vivo tissue sections and other in vitro models
• Identification of radiation-induced signalling pathways by integrative bioinformatic analyses in exposed tissues

This knowledge will be used to refine risk assessment models, particularly in occupational and medical radiation protection.

Implementation

The project investigates the effects of radiation on target cells and the microenvironment. For example, the development of medulloblastomas is studied using a Ptch+/- model system. This established model exhibits an increased incidence of medulloblastomas following radiation exposure. In addition, the disease manifests after a shorter latency period. Direct radiation effects on target cells (e.g. epigenetic and proteome changes) are investigated. Systemic effects, including cytokine release, changes in the extracellular matrix, and local immune responses, are also considered.

The established model system will be investigated using state-of-the-art multi-omics analysis methods and associated bioinformatics pipelines. The aim is to systematically investigate changes in the microenvironment of the brain and the role of extracellular vesicles in the development of radiation-induced carcinogenesis – also from the perspective of dose dependence.

By integrating innovative approaches and comparing them with clinical data, researchers aim to greatly enhance our understanding of radiation-induced cancer, its potential effects, and its applications in risk assessment and personalised medicine.

The seven work packages

The DISCOVER project consists of seven work packages (WPs):

• WP1: Investigation of changes in the microenvironment of the cerebellum after radiation exposure
• WP2: Investigation of radiation effects on target cells and the microenvironment in the cerebellum
• WP3: Investigation of the effects of ionising radiation on granular precursor cells and their microenvironment
• WP4: Identification of key factors in radiation-induced signalling pathways
• WP5: Mode of action of extracellular vesicles and other influencing factors
• WP6: Coordination and scientific project management
• WP7: Dissemination and utilisation of the results