Speaker
Descrizione
Background and Aim: The molecular mechanisms underlying the FLASH effect remain largely unknown. We previously demonstrated that electron FLASH radiotherapy (FLASH-RT) achieves tumor control comparable to conventional radiotherapy (CONV-RT) in a murine melanoma model, while significantly reducing damage to surrounding skin. Here, we investigated the molecular and histological correlates of this sparing effect, extending our analysis to adjacent tissues and systemic parameters.
Methods: Healthy mice received 35 Gy to the posterior leg using either CONV or FLASH modes via a low-energy LINAC equipped with a triode-gun Electron-Flash system. Skin, white adipose tissue (WAT), and muscle from the irradiated area were collected at sacrifice and analyzed by RNA sequencing, optical microscopy, and transmission electron microscopy. Mice were monitored for 20 weeks post-treatment to assess circulating metabolic and inflammatory markers.
Results: CONV-RT and FLASH-RT altered the expression of 2,461 and 93 genes, respectively, in the skin. Pathway analysis of upregulated genes revealed no enriched terms specific to FLASH-RT, whereas 81 enriched pathways were identified in the CONV-RT group, mainly related to inflammation, fibrosis, and cell death. In WAT, transcriptomic signatures indicated reduced functionality following CONV-RT but not FLASH-RT. In muscle, key protein synthesis pathways (mTOR, Akt, S6) were altered only in CONV-treated mice. These molecular findings were corroborated by histological analyses. At the systemic level, CONV-RT mice showed decreased levels of the satiety hormone leptin and increased levels of the appetite stimulator ghrelin. FLASH-RT mice showed no such alterations.
Conclusions: Our findings highlight a marked difference in tissue and systemic responses between CONV-RT and FLASH-RT. FLASH-RT minimizes inflammatory and metabolic disruptions in normal tissues, supporting its therapeutic potential for reducing radiotoxicity without compromising tumor control.
Aknowledgements: FPS, PNRR-THE, MIRO
