Author Of 1 Presentation
PROTON AND PHOTON IRRADIATION INDUCE DIFFERENT SALIVARY GLAND ORGANOID INFLAMMASOME RESPONSE.
Abstract
Background and Aims
Little is known about the mechanism of the biologically proton versus photon irradiation in healthy tissue. Differences in DNA double strand breaks could initiate a distinct secondary response of normal tissue cells, such as the initiation of senescence. To investigate these potential differences between proton and photon irradiation, we used our murine salivary gland organoid model that closely resembles the in vivo response after irradiation.
Methods
First, we established the induction of senescence and senescence-related genes upon both proton and photon irradiation using SA-b-Gal, p16 and p21 as markers.
Results
Interestingly, no differences were observed in the initiation of senescence. However, bulk RNA sequencing showed clear distinctive transcriptome profiles at different time points and radiation doses, especially the inflammatory response. Significant differences were observed in genes related to cytoplasmatic dsDNA and dsRNA recognition, immunity activation, Interferon 1 (IFN1) response and tissue development. Next to this, proton irradiation enhanced cGAS-related signalling, the number of micronuclei containing both cGAS and dsDNA and both cytoplasmic dsRNA and genes related to cytosolic dsRNA sensing. All this coincided with a higher expression of Interferon stimulated genes.
Conclusions
Our study suggests that the DNA damage induced by proton irradiation might lead to more dsDNA leakage into the cytoplasm and consequently more cGAS activation. This might lead to a more pronounced activation of Interferon stimulated genes and dsRNA release that act as positive feedback for the activation of immune responses and inflammation. This enhanced cellular immune response could lead to dissimilar normal tissue response to proton versus photon irradiation.