Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation

Microenvironmental stiffness regulates fundamental aspects of cell behaviour, including proliferation, differentiation and metabolism, many of which are implicated in cancer initiation and progression. In the mammary gland, extracellular matrix (ECM) stiffness, associated with high mammographic density, is linked to increased breast cancer incidence. However, a mechanistic link between increased ECM stiffness and the genomic damage required for transforming mutations remains unclear. Here we show that ECM stiffness induces changes in mammary epithelial cell (MEC) metabolism which drive DNA damage. Using a mechanically tunable 3D-culture model, we demonstrate that transcriptional changes in response to increased ECM stiffness impair the ability of MECs to remove reactive aldehydes. Downregulation of multiple aldehyde dehydrogenase isoforms in MECs within a stiffer 3D ECM leads to higher levels of reactive aldehydes, resulting in genomic damage and transformation. Together, these results provide a mechanistic link between increased ECM stiffness and the genomic damage required for breast cancer initiation.

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Publication Details

Journal
Scientific Reports
Published
2025-08-09
DOI
https://doi.org/10.1038/s41598-025-12880-0
Primary Topic
Cancer Cells and Metastasis
Type
article
Field-Weighted Citation Impact
0.00

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article

Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation

Eldhose Skaria, Heyuan Sun, Eleanor Broadberry, Charles Streuli et al.
Scientific Reports
Cancer Cells and Metastasis
article

Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation

Eldhose Skaria, Heyuan Sun, Eleanor Broadberry, Charles Streuli, Howard B. Barnes, Andrew Gilmore, Alis Hales, Amber Wood, Joe Swift, Hannah Percival, Craig Lawless, Keith Brennan, Egor Zindy, Matt Jones, Fabianna Tennant
article en

Abstract

Microenvironmental stiffness regulates fundamental aspects of cell behaviour, including proliferation, differentiation and metabolism, many of which are implicated in cancer initiation and progression. In the mammary gland, extracellular matrix (ECM) stiffness, associated with high mammographic density, is linked to increased breast cancer incidence. However, a mechanistic link between increased ECM stiffness and the genomic damage required for transforming mutations remains unclear. Here we show that ECM stiffness induces changes in mammary epithelial cell (MEC) metabolism which drive DNA damage. Using a mechanically tunable 3D-culture model, we demonstrate that transcriptional changes in response to increased ECM stiffness impair the ability of MECs to remove reactive aldehydes. Downregulation of multiple aldehyde dehydrogenase isoforms in MECs within a stiffer 3D ECM leads to higher levels of reactive aldehydes, resulting in genomic damage and transformation. Together, these results provide a mechanistic link between increased ECM stiffness and the genomic damage required for breast cancer initiation.

Scientific ReportsVol. 15(1)
Université Libre de Bruxelles (BE), Manchester Academic Health Science Centre (GB), Wellcome Centre for Cell-Matrix Research (GB), University of Manchester (GB), Henry Royce Institute (GB)
Wellcome Trust, Cancer Research UK, Cancer Research UK Manchester Centre, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council
Good health and well-being
Openalex Percentile: Top 71%
Cancer Cells and Metastasis
DOIOpen Access PDFOpenAlex
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