NOTCH signaling promotes the survival of irradiated basal airway stem cells

Lorena Giuranno, Carolien Wansleeben, Raffaella Iannone, Louise Arathoon, Judith Hounjet, Arjan J. Groot, Marc Vooijs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

Abstract

Radiation-induced lung injury to normal airway epithelium is a frequent side-effect and dose-limiting factor in radiotherapy of tumors in the thoracic cavity. NOTCH signaling plays key roles in self-renewal and differentiation of upper airway basal lung stem cells during development, and the NOTCH pathway is frequently deregulated in lung cancer. In preclinical lung cancer models, NOTCH inhibition was shown to improve the radiotherapy response by targeting tumor stem cells, but the effects in combination with irradiation on normal lung stem cells are unknown. NOTCH/gamma-secretase inhibitors are potent clinical candidates to block NOTCH function in tumors, but their clinical implementation has been hampered by normal tissue side-effects. Here we show that NOTCH signaling is active in primary human-and murine-derived airway epithelial stem cell models and when combined with radiation NOTCH inhibition provokes a decrease in S-phase and increase in G(1)-phase arrest. We show that NOTCH inhibition in irradiated lung basal stem cells leads to a more potent activation of the DNA damage checkpoint kinases pATM and pCHK2 and results in an increased level of residual 53BP1 foci in irradiated lung basal stem cells reducing their capacity for self-renewal. The effects are recapitulated in ex vivo cultured lung basal stem cells after in vivo whole thorax irradiation and NOTCH inhibition. These results highlight the importance of studying normal tissue effects that may counteract the therapeutic benefit in the use of NOTCH/gamma-secretase inhibitors in combination with radiation for antitumor treatment.

Original languageEnglish
Pages (from-to)L414-L423
Number of pages10
JournalAmerican Journal of Physiology-Lung Cellular and Molecular Physiology
Volume317
Issue number3
DOIs
Publication statusPublished - Sep 2019

Keywords

  • basal stem cells
  • DNA damage response
  • lung organoids
  • NOTCH signaling
  • primary bronchial epithelial cells
  • radiation-induced lung injury
  • radiotherapy
  • SECRETASE INHIBITION
  • LUNG
  • RADIATION
  • REGENERATION
  • DIFFERENTIATION
  • ACTIVATION
  • CLARA
  • HOMEOSTASIS
  • MECHANISMS
  • REGULATOR

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