TY - JOUR
T1 - FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
AU - Fouillade, Charles
AU - Curras-Alonso, Sandra
AU - Giuranno, Lorena
AU - Quelennec, Eddy
AU - Heinrich, Sophie
AU - Bonnet-Boissinot, Sarah
AU - Beddok, Arnaud
AU - Leboucher, Sophie
AU - Karakurt, Hamza Umut
AU - Bohec, Mylène
AU - Baulande, Sylvain
AU - Vooijs, Marc
AU - Verrelle, Pierre
AU - Dutreix, Marie
AU - Londoño-Vallejo, Arturo
AU - Favaudon, Vincent
N1 - ©2019 American Association for Cancer Research.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - PURPOSE: One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity.EXPERIMENTAL DESIGN: Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc-/- mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro.RESULTS: In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc-/- mice harboring critically short telomeres and lack of telomerase activity.CONCLUSIONS: The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.
AB - PURPOSE: One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity.EXPERIMENTAL DESIGN: Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc-/- mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro.RESULTS: In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc-/- mice harboring critically short telomeres and lack of telomerase activity.CONCLUSIONS: The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.
KW - STEM-CELLS
KW - RADIATION
KW - PROMOTES
KW - TELOMERE
KW - 53BP1
KW - MICE
U2 - 10.1158/1078-0432.ccr-19-1440
DO - 10.1158/1078-0432.ccr-19-1440
M3 - Article
C2 - 31796518
SN - 1078-0432
VL - 26
SP - 1497
EP - 1506
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -