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Radiation-induced senescence: application to lung stereotactic body radiation therapy

​Frédéric Soysouvanh has defended his thesis on 24th January 2019 at IRSN, in Fontenay-aux-Roses, France.

Document type > *Mémoire/HDR/Thesis

Keywords >

Research Unit > IRSN/PSE-SANTÉ/SERAMED/LRMed

Authors > SOYSOUVANH Frédéric

Publication Date > 24/01/2019

Summary

​Radiotherapy is the main modality in cancer treatment but is associated with radiation damages on healthy tissues. Endothelial cells (ECs) play a key role in the evolution of radiation-induced normal tissue injuries. Cellular senescence is a powerful tumor suppressor mechanism but, paradoxically, long-term senescence can be deleterious for tissue homeostasis. The presence of senescent cells within the radiation-induced lesions has been shown but their role is not well understood. We aimed to identify and understand the molecular mechanisms involved in radiation-induced senescence and its role in radiation-induced lung injuries after stereotactic irradiation. In vivo, using luciferase knock-in mice (p16Ink4-LUC) to detect activation of a senescence player, we explored the presence of senescent cells in radiation-induced pulmonary injury after a stereotactic irradiation performed with a Small Animal Radiation Research Platform. After single/fractionated high-dose lung irradiation of p16Ink4-LUC mice and using bioluminescence imaging we showed the overexpression of p16 in the irradiation field and its persistence up to 21 months after radiation exposure. Immunostainings revealed a panel of heterogeneous senescent cells including pneumocytes, macrophages and endothelial cells (EC). mRNA expression of 44 genes involved in senescence in 6 human primary irradiated ECs revealed that Human Umbilical Vein Endothelial Cells (HUVECs) are the most relevant in term of gene expression. The dynamic molecular profile associated to radiation-induced senescence (RIS) in HUVECs was analyzed after 9 doses and 7 time points. Using a deep analysis by mathematical/bioinformatics methods, we deciphered the dynamical transcriptional program involved in RIS and we identified IL1-signaling pathway as a key molecular hub which could potentially modulate the senescence phenotype.


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