Unraveling the radiobiology of protons and photons – using the model organism S. cerevisiae

Ever since the discovery of X-rays in 1895 by William Röntgen, radiotherapy has been a cornerstone in the cancer treatment. Nowadays, up to 50% of cancer patients are treated with radiotherapy during their course of illness. Despite many technical improvements in radiotherapy planning and delivery, X-ray or photon radiotherapy (XRT) is still associated with toxicity to normal tissue surrounding the tumor. Proton radiotherapy (PRT) is emerging as an alternative radiation treatment with the potential to reduce the normal tissue toxicity associated with conventional photon-based radiotherapy. The positive charge and mass of the protons result in a very characteristic depth-dose profile called the Bragg peak. This makes targeted radiation delivery possible, which leads to reduced normal tissue toxicity without compromising radiation dose to the tumor.

Although this dosimetric advantage of PRT is well known, the molecular mechanisms affected by PRT remain largely elusive. Increased knowledge of the molecular pathways affected by PRT can lead to selective targeted therapy combinations. This is relevant in the field of personalized medicine because understanding the radiobiology of protons and its interaction with the complex biology of the tumor will allow for the integration of clinical, physical and biological parameters to adjust treatment to the specific needs of an individual patient. A system-wide approach, which is often missing, could help bring more insights into the molecular mechanisms affected by treatment with PRT.

Therefore, in this study, for the first time, we apply an integrated approach to identify the exact mechanisms and cellular pathways affected by both PRT and XRT using the unicellular eukaryote Saccharomyces cerevisiae as a model. The short life cycle, simple culture conditions and ease with which the genome can be manipulated make S. cerevisiae an extensively used model organism, not only in radiobiology but in medicine in general. Using Bar-Seq in combination with more detailed molecular assays, we found that genes involved in DNA repair determined the survival of cells exposed to XRT and PRT. Moreover, the DNA damage response was equally important for both irradiation types. Remarkably, in contrast to XRT, transcriptomic analysis after PRT showed a much stronger activation of genes involved in the response to proteotoxic stress. Additionally, inhibition of the proteasome resulted in decreased survival after PRT, but not after XRT. Altogether, our results offer a genome-wide view on the physiological effects of PRT and XRT and bridge the gap between current biological uncertainties and the translation of PRT to the clinic.