Spatial gene expression changes in the mouse heart after base-targeted irradiation

Gerard M. Walls; Mihaela Ghita; Rachel Queen; Kevin S. Edgar; Eleanor K. Gill; Refik Kuburas; David J. Grieve; Chris J. Watson; Alan McWilliam; Marcel Van Herk; Kaye J. Williams; Aidan J. Cole; Suneil Jain; Karl T. Butterworth

doi:10.1016/j.ijrobp.2022.08.031

Spatial gene expression changes in the mouse heart after base-targeted irradiation

Gerard M. Walls^*, Mihaela Ghita, Rachel Queen, Kevin S. Edgar, Eleanor K. Gill, Refik Kuburas, David J. Grieve, Chris J. Watson, Alan McWilliam, Marcel Van Herk, Kaye J. Williams, Aidan J. Cole, Suneil Jain, Karl T. Butterworth

^*Corresponding author for this work

School of Medicine, Dentistry and Biomedical Sciences

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

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Abstract

Purpose: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity.

Methods and Materials: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions.

Results: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities.

Conclusions: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.

Original language	English
Pages (from-to)	453-463
Number of pages	11
Journal	International Journal of Radiation Oncology Biology Physics
Volume	115
Issue number	2
Early online date	06 Jan 2023
DOIs	https://doi.org/10.1016/j.ijrobp.2022.08.031
Publication status	Published - 01 Feb 2023

Bibliographical note

Funding Information:
This work was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland (GW, AC, SJ, KB). MG, RF and KB are supported by the Medical Research Council (MR/V009605/1). EG, KE, DG and CW are supported by the British Heart Foundation. RQ is supported by the Spartan Programme. AM, MV and KW are supported by the Cancer Research UK RadNet Manchester programme [C1994/A28701], and AM and MV also receive support from the NIHR Manchester Biomedical Research Centre.

Publisher Copyright:
© 2022 The Author(s)

ASJC Scopus subject areas

Radiation
Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

UN SDGs

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

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10.1016/j.ijrobp.2022.08.031Licence: CC BY

Spatial gene expression changes in the mouse heart after base-targeted irradiation
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.17 MBLicence: CC BY

Biophysical correlates of base-mediated radiation cardiotoxicity in non-small cell lung cancer
Author: Walls, G. M., Jul 2023
Supervisor: Butterworth, K. (Supervisor), Jain, S. (Supervisor) & Cole, A. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy

Cite this

Walls, G. M., Ghita, M., Queen, R., Edgar, K. S., Gill, E. K., Kuburas, R., Grieve, D. J., Watson, C. J., McWilliam, A., Van Herk, M., Williams, K. J., Cole, A. J., Jain, S., & Butterworth, K. T. (2023). Spatial gene expression changes in the mouse heart after base-targeted irradiation. International Journal of Radiation Oncology Biology Physics, 115(2), 453-463. https://doi.org/10.1016/j.ijrobp.2022.08.031

@article{77fa0ddf058e46fbaee776ef9cb31b55,

title = "Spatial gene expression changes in the mouse heart after base-targeted irradiation",

abstract = "Purpose: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. Methods and Materials: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. Results: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities. Conclusions: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.",

author = "Walls, {Gerard M.} and Mihaela Ghita and Rachel Queen and Edgar, {Kevin S.} and Gill, {Eleanor K.} and Refik Kuburas and Grieve, {David J.} and Watson, {Chris J.} and Alan McWilliam and {Van Herk}, Marcel and Williams, {Kaye J.} and Cole, {Aidan J.} and Suneil Jain and Butterworth, {Karl T.}",

note = "Funding Information: This work was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland (GW, AC, SJ, KB). MG, RF and KB are supported by the Medical Research Council (MR/V009605/1). EG, KE, DG and CW are supported by the British Heart Foundation. RQ is supported by the Spartan Programme. AM, MV and KW are supported by the Cancer Research UK RadNet Manchester programme [C1994/A28701], and AM and MV also receive support from the NIHR Manchester Biomedical Research Centre. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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Walls, GM , Ghita, M, Queen, R, Edgar, KS, Gill, EK, Kuburas, R , Grieve, DJ , Watson, CJ, McWilliam, A, Van Herk, M, Williams, KJ, Cole, AJ , Jain, S & Butterworth, KT 2023, 'Spatial gene expression changes in the mouse heart after base-targeted irradiation', International Journal of Radiation Oncology Biology Physics, vol. 115, no. 2, pp. 453-463. https://doi.org/10.1016/j.ijrobp.2022.08.031

TY - JOUR

T1 - Spatial gene expression changes in the mouse heart after base-targeted irradiation

AU - Walls, Gerard M.

AU - Ghita, Mihaela

AU - Queen, Rachel

AU - Edgar, Kevin S.

AU - Gill, Eleanor K.

AU - Kuburas, Refik

AU - Grieve, David J.

AU - Watson, Chris J.

AU - McWilliam, Alan

AU - Van Herk, Marcel

AU - Williams, Kaye J.

AU - Cole, Aidan J.

AU - Jain, Suneil

AU - Butterworth, Karl T.

N1 - Funding Information: This work was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland (GW, AC, SJ, KB). MG, RF and KB are supported by the Medical Research Council (MR/V009605/1). EG, KE, DG and CW are supported by the British Heart Foundation. RQ is supported by the Spartan Programme. AM, MV and KW are supported by the Cancer Research UK RadNet Manchester programme [C1994/A28701], and AM and MV also receive support from the NIHR Manchester Biomedical Research Centre. Publisher Copyright: © 2022 The Author(s)

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Purpose: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. Methods and Materials: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. Results: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities. Conclusions: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.

AB - Purpose: Radiation cardiotoxicity (RC) is a clinically significant adverse effect of treatment for patients with thoracic malignancies. Clinical studies in lung cancer have indicated that heart substructures are not uniformly radiosensitive, and that dose to the heart base drives RC. In this study, we aimed to characterize late changes in gene expression using spatial transcriptomics in a mouse model of base regional radiosensitivity. Methods and Materials: An aged female C57BL/6 mouse was irradiated with 16 Gy delivered to the cranial third of the heart using a 6 × 9 mm parallel opposed beam geometry on a small animal radiation research platform, and a second mouse was sham-irradiated. After echocardiography, whole hearts were collected at 30 weeks for spatial transcriptomic analysis to map gene expression changes occurring in different regions of the partially irradiated heart. Cardiac regions were manually annotated on the capture slides and the gene expression profiles compared across different regions. Results: Ejection fraction was reduced at 30 weeks after a 16 Gy irradiation to the heart base, compared with the sham-irradiated controls. There were markedly more significant gene expression changes within the irradiated regions compared with nonirradiated regions. Variation was observed in the transcriptomic effects of radiation on different cardiac base structures (eg, between the right atrium [n = 86 dysregulated genes], left atrium [n = 96 dysregulated genes], and the vasculature [n = 129 dysregulated genes]). Disrupted biological processes spanned extracellular matrix as well as circulatory, neuronal, and contractility activities. Conclusions: This is the first study to report spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation response in the heart can help to further our understanding of the cardiac base's radiosensitivity and support the development of actionable targets for pharmacologic intervention and biologically relevant dose constraints.

U2 - 10.1016/j.ijrobp.2022.08.031

DO - 10.1016/j.ijrobp.2022.08.031

M3 - Article

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VL - 115

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JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

IS - 2

ER -

Spatial gene expression changes in the mouse heart after base-targeted irradiation

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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Student theses

Biophysical correlates of base-mediated radiation cardiotoxicity in non-small cell lung cancer

Cite this