A matter of space: how the spatial heterogeneity in energy deposition determines the biological outcome of radiation exposure

Abstract

The outcome of the exposure of living organisms to ionizing radiation is determined by the distribution of the associated energy deposition at different spatial scales. Radiation proceeds through ionizations and excitations of hit molecules with an ~ nm spacing. Approaches such as nanodosimetry/microdosimetry and Monte Carlo track-structure simulations have been successfully adopted to investigate radiation quality effects: they allow to explore correlations between the spatial clustering of such energy depositions at the scales of DNA or chromosome domains and their biological consequences at the cellular level. Physical features alone, however, are not enough to assess the entity and complexity of radiation-induced DNA damage: this latter is the result of an interplay between radiation track structure and the spatial architecture of chromatin, and further depends on the chromatin dynamic response, affecting the activation and efficiency of the repair machinery. The heterogeneity of radiation energy depositions at the single-cell level affects the trade-off between cell inactivation and induction of viable mutations and hence influences radiation-induced carcinogenesis. In radiation therapy, where the goal is cancer cell inactivation, the delivery of a homogenous dose to the tumour has been the traditional approach in clinical practice. However, evidence is accumulating that introducing heterogeneity with spatially fractionated beams (mini- and microbeam therapy) can lead to significant advantages, particularly in sparing normal tissues. Such findings cannot be explained in merely physical terms, and their interpretation requires considering the scales at play in the underlying biological mechanisms, suggesting a systemic response to radiation.

Keywords: DNA damage and repair; Ionizing radiation; Micro- and nanodosimetry; Radiation track structure; Relative biological effectiveness; Spatially fractionated radiation therapy.

Fig. 1

Comparison between the ratio ${\overline{y}}_{D,d}/{\overline{y}}_{D,7.5\mathrm{mm}}$ at different site sizes, where ${\overline{y}}_{D,d}$ is the dose-mean lineal energy measured at depth d, and the reference value ${\overline{y}}_{D,7.5\mathrm{mm}}$ is the mean-dose lineal energy at a depth of 7.5 mm. RBE values for a survival fraction of 10% (RBE₁₀) for cells irradiated at the same beam line are also shown for comparison. Figure data adapted from Mazzucconi (2019). RBE data from Chaudhary et al. (2014)

Fig. 2

Relevant spatial scales for radiation damage formation. a Formation of DSBs arises from secondary electrons inducing two adjacent SSBs in a correlated manner (red) within some nm, but also a concerted action of distinct electrons from the same high-LET track may result in a DSB at high ionization densities (blue). b Proximity of DSBs on the µm scale may result in more complex lesions modifying the integrity of the DNA structure (e.g. Mbp chromatin loops) or reduce repair probability by enhanced mis-rejoining options. c Hit statistics in the order of nuclear sizes (~ 10 µm) determines a fraction of unhit cells (green) not affected by radiation (except potential bystander effects) (color figure online)

Fig. 3

Examples of fluorescence images of RIFs using different DNA damage markers as surrogates of DSBs and simulated DSB distributions using the local effect model LEM IV. a, top Direct labelling of DNA strand breaks using TUNEL (green) and co-staining with XRCC1 (red)/Dapi (blue) 5 min after irradiation with 6 MeV/u Au (LET ~ 13,000 keV/µm). b, top 53BP1 (red) and the resection marker RPA (green)/Dapi (blue) 5 h after irradiation with 500 MeV/u Xe (LET ~ 800 keV/µm). c, top NBS1-GFP in living U2OS cells 2 min after irradiation with 1 GeV/u Fe [LET ~ 150 keV/µm; modified from (Jakob et al. 2020)]. Lower row, a–c Corresponding simulations of DSB distribution along a single ion trajectory for the given ion and energy combinations using LEM IV. The cell nuclei were modelled as a homogeneously chromatin filled cylinder with 3.15 µm radius and 16 µm height (color figure online)

Fig. 4

a Typical dose profile of a microbeam treatment field with 50 µm beam width and 400 µm spacing (digitalized radiochromic film reading). b Schematic setup of an MRT treatment: the homogeneous synchrotron X-ray field is shaped by a collimator in multiple micrometre-sized planar beamlets. (a, b from Bartzsch et al. 2020) c) H&E stained tissue section the rat spinal cord after treatment with microbeams (Laissue et al. 2013). d) Normal chicken chorioallantoic membrane after microbeam exposure showing localized leakage of the vasculature (Sabatasso et al. 2021)