Jones Matthew, Percival Hannah, Hales Alis, Wood Amber, Sun Heyuan, Tennant Fabianna, Broadberry Eleanor, Skaria Eldhose, Barnes Harry, Zindy Egor, Lawless Craig, Streuli Charles, Swift Joe, Brennan Keith, Gilmore Andrew P
Manchester Cell Matrix Centre, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Sci Rep. 2025 Aug 9;15(1):29127. doi: 10.1038/s41598-025-12880-0.
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.
微环境硬度调节细胞行为的基本方面，包括增殖、分化和代谢，其中许多与癌症的发生和进展有关。在乳腺中，与高乳腺X线密度相关的细胞外基质（ECM）硬度与乳腺癌发病率增加有关。然而，ECM硬度增加与转化突变所需的基因组损伤之间的机制联系仍不清楚。在这里，我们表明ECM硬度会诱导乳腺上皮细胞（MEC）代谢变化，从而导致DNA损伤。使用机械可调的3D培养模型，我们证明了对增加的ECM硬度的转录变化会损害MEC去除反应性醛的能力。在更硬的3D ECM中，MEC中多种醛脱氢酶同工型的下调导致更高水平的反应性醛，从而导致基因组损伤和转化。总之，这些结果提供了ECM硬度增加与乳腺癌起始所需的基因组损伤之间的机制联系。
