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Spatial Gene Expression Changes in the Mouse Heart After Base-targeted Irradiation

Lookup NU author(s): Dr Rachel Queen

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2022 The Author(s)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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: International Journal of Radiation Oncology*Biology*Physics

Year: 2023

Volume: 115

Issue: 2

Pages: 453-463

Print publication date: 01/02/2023

Online publication date: 17/08/2022

Acceptance date: 05/08/2022

Date deposited: 31/08/2023

ISSN (print): 0360-3016

ISSN (electronic): 1879-355X

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.ijrobp.2022.08.031

DOI: 10.1016/j.ijrobp.2022.08.031

PubMed id: 35985456


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Funding

Funder referenceFunder name
BRC
British Heart Foundation
Cancer Research UK
Health Research Board (Grant Number 203930/B/16/Z)
MR/V009605/1
MRC
RadNet Manchester programme [C1994/A28701]
NIHR
Spartan Programme
Wellcome Trust

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