Pre-existing subclones determine radioresistance in rectal cancer organoids

Daan Andel; Bas Jeroen Viergever; Niek Alexander Peters; Danielle Adriana Elisabeth Raats; Susanne Jolien Schenning-van Schelven; Martijn Peter Willem Intven; Maurice Zandvliet; Jeroen Hagendoorn; Inne Hildbrand Max Borel Rinkes; Onno Kranenburg

doi:10.1016/j.celrep.2024.113735

Pre-existing subclones determine radioresistance in rectal cancer organoids

Daan Andel, Bas Jeroen Viergever, Niek Alexander Peters, Danielle Adriana Elisabeth Raats, Susanne Jolien Schenning-van Schelven, Martijn Peter Willem Intven, Maurice Zandvliet, Jeroen Hagendoorn, Inne Hildbrand Max Borel Rinkes^*, Onno Kranenburg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	113735
Journal	Cell Reports
Volume	43
Issue number	2
Early online date	2 Feb 2024
DOIs	https://doi.org/10.1016/j.celrep.2024.113735
Publication status	Published - 27 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Funding

The authors would like to express their gratitude to Geert Kops and Nico Lansu for their valuable scientific insights and code sharing and Joshua Peterson and Floris Leendert for their support during the single-cell experiments. Special gratitude goes toward André Wopereis, Wilfred de Vries, Ingrid Boots, Marjolijn Gross, and Masha de Koning-Hoogeboom for their practical insights and assistance with the irradiation of organoids. This research was funded by a private fund.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.113735Licence: CC BY

1-s2.0-S2211124724000639-mainFinal published version, 19 MBLicence: CC BY

Cite this

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title = "Pre-existing subclones determine radioresistance in rectal cancer organoids",

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.",

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AU - Andel, Daan

AU - Viergever, Bas Jeroen

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AU - Schenning-van Schelven, Susanne Jolien

AU - Willem Intven, Martijn Peter

AU - Zandvliet, Maurice

AU - Hagendoorn, Jeroen

AU - Max Borel Rinkes, Inne Hildbrand

AU - Kranenburg, Onno

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N2 - 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.

AB - 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.

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Pre-existing subclones determine radioresistance in rectal cancer organoids

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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