Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)
228 Downloads (Pure)

Abstract

Purpose: Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function.

Experimental Design: Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification.

Results: Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses = 1 Gy, was observed in salivary gland and thyroid gland organoid cultures. DDR modulation resulted in diminished, or even abrogated, relative radioresistance. Furthermore, inhibition of the DDR protein ATM impaired DNA repair after 1 Gy, but not 0.25 Gy. Irradiation of patient-derived salivary gland organoid cells showed similar responses, whereas a single 1 Gy dose to salivary gland-derived stem cells resulted in greater survival than clinically relevant fractionated doses of 4 x 0.25 Gy.

Conclusions: We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation. (C) 2018 AACR.

Original languageEnglish
Pages (from-to)6583-6593
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number24
Early online date22-Aug-2018
DOIs
Publication statusPublished - 15-Dec-2018

Keywords

  • DOUBLE-STRAND BREAKS
  • IN-VITRO
  • INCREASED RADIORESISTANCE
  • MODELING DEVELOPMENT
  • EXPANSION
  • IMPACT
  • ATM
  • HYPERSENSITIVITY
  • RADIOSENSITIVITY
  • RADIOTHERAPY

Fingerprint

Dive into the research topics of 'Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction'. Together they form a unique fingerprint.

Cite this