Pre-existing subclones determine radioresistance in rectal cancer organoids

Daan Andel, Bas Viergever, Niek Peters, Danielle Raats, Susanne Schenning-van Schelven, Martijn Intven, Maurice Zandvliet, Jeroen Hagendoorn, Inne Borel Rinkes*, Onno Kranenburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

More than half of all patients with cancer receive radiation therapy, but resistance is commonly observed. Currently, it is unknown whether resistance to radiation therapy is acquired or inherently present. Here, we employed organoids derived from rectal cancer and single-cell whole-genome sequencing to investigate the long-term evolution of subclones in response to radiation. Comparing single-cell whole-genome karyotypes between in-vitro-unirradiated and -irradiated organoids revealed three patterns of subclonal evolution: (1) subclonal persistence, (2) subclonal extinction, and (3) subclonal expansion. Organoids in which subclonal shifts occurred (i.e., expansion or extinction) became more resistant to radiation. Although radioresistant subclones did not share recurrent copy-number alterations that could explain their radioresistance, resistance was associated with reduced chromosomal instability, an association that was also observed in 529 human cancer cell lines. These data suggest that resistance to radiation is inherently present and associated with reduced chromosomal instability.

Original languageEnglish
Article number113735
Number of pages13
JournalCell Reports
Volume43
Issue number2
Early online date2 Feb 2024
DOIs
Publication statusPublished - 27 Feb 2024

Keywords

  • CP: Cancer
  • patient-derived organoids
  • radioresistance
  • rectal cancer
  • single-cell sequencing
  • tumor evolution

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