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Enhancing Nuclear Safety


Research

Thesis vivas

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


 

Frédéric Soysouvanh will defend his thesis

on Thursday 24th January 2019 at 1:30 pm

at IRSN, auditorium (building 01)

31 avenue de la Division Leclerc

92260 Fontenay-aux-Roses

France

 

 

Jury

 

Pr. Isabelle PETROPOULOS, Jury President

Dr. David BERNARD, reporter

Dr. François PARIS, reporter

Dr. Nazanine MODJTAHEDI, examiner

Pr. Jacques BALOSSO, examiner

Dr. Fabien MILLIAT, thesis supervisor


 

Abstract

 

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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