EDA2R Elevation in Liquid Biopsy Reflects Acute Brain Injury after Cranial Radiation

Background

Cranial radiation therapy is the standard treatment for advanced brain tumors and metastases, but it leads to devastating neurocognitive impairments, especially in childhood cancer survivors. As the number of childhood brain cancer survivors continues to rise, more and more individuals are expected to suffer lifelong neurocognitive sequelae. However, there is currently no established biomarker to assess the extent of radiation-induced brain injury at the end of radiation therapy, thereby predicting the expected severity of neurocognitive complications.

Research Institute and Authors

This research was conducted by Alejandro Lastra Romero, Thea Seitz, Georgios Alkis Zisiadis, Holli Jeffery, and Ahmed M. Osman from the Department of Women’s and Children’s Health, Karolinska Institutet, Sweden.

Research Methods and Process

a) Research workflow: The study employed a juvenile mouse model of cranial radiation. Mice received cranial irradiation at doses of 0.5, 1, 2, 4, and 8 Gy, and cerebrospinal fluid, plasma, and brain tissue samples were collected at acute (6 hours), subacute (2 weeks), and subchronic (6 weeks) time points for proteomic screening, molecular, and histological analyses.

b) Key research findings: The study found that the levels of the tumor necrosis factor receptor superfamily member EDA2R (ectodysplasin A2 receptor) were significantly elevated in the cerebrospinal fluid and brain tissue after radiation, even at lower doses. EDA2R expression was upregulated in the whole brain at the acute phase and gradually decreased over time. EDA2R was primarily expressed by neurons, and its temporal dynamics in brain tissue were also reflected in plasma samples.

c) Research conclusions: The researchers propose that EDA2R may serve as a potential biomarker for radiation-induced brain injury, measurable through liquid biopsy. The levels of EDA2R at the end of radiation therapy may help predict the severity of radiation-induced neurocognitive complications at an early stage.

Research Significance and Innovation

This preclinical study is the first to describe the spatiotemporal expression pattern of EDA2R after cranial radiation in an in vivo model, as well as the dynamic reflection of these molecular events in body fluids (cerebrospinal fluid and plasma). The study identified EDA2R as a potential biomarker for assessing acute brain responses to cranial radiation.

This finding has important clinical translational implications, as currently, there is no established biomarker to assess the extent of radiation-induced brain injury at the end of radiation therapy, thereby predicting the expected neurocognitive complications. If validated in clinical samples, the post-radiation assessment of EDA2R holds promise for predicting the severity of neurocognitive impairments in children after radiation therapy, guiding preventive or therapeutic interventions.

In summary, the study discovered a novel liquid biopsy biomarker that reflects acute brain injury induced by cranial radiation, providing new potential opportunities to mitigate complications in pediatric radiation therapy.