2. Academic Validation
  3. Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage

Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage

  • Cancer Cell. 2026 Jun 8;44(6):1255-1269.e9. doi: 10.1016/j.ccell.2026.03.022.
Mary-Kate Hayward 1,  Jason J Northey 2,  Valentina Opazo-Mellado 3,  Connor Stashko 1,  Ori Maller 1,  Alastair J Ironside 4,  Xuchu Que 5,  Jonathon N Lakins 1,  E Shelley Hwang 6,  Joseph L Witztum 5,  Hugo Gonzalez 7,  Valerie M Weaver 8
Affiliations

Affiliations

  • 1 Department of Surgery, University of California, San Francisco, San Francisco, CA, USA; Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA, USA.
  • 2 Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
  • 3 Centro BASAL Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile.
  • 4 Department of Pathology, Western General Hospital, NHS Lothian, Edinburgh, UK.
  • 5 Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 6 Department of Surgery, Duke University Medical Center, Durham, NC, USA.
  • 7 Centro BASAL Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile; Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Santiago, Chile; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA; UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 8 Department of Surgery, University of California, San Francisco, San Francisco, CA, USA; Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA, USA; UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
PMID: 42066761 DOI: 10.1016/j.ccell.2026.03.022
Abstract

Inflammation can induce mutagenic DNA damage to enhance Cancer risk and progression. Inflammation also increases fibrosis and stromal stiffening that promotes malignancy, and tissues with higher Cancer risk are often stiffer. Despite this connection, how stromal stiffness contributes to inflammatory-mediated DNA damage in tumorigenesis remains unclear. Here, we show that tissue tension engages macrophages to generate lipid peroxidation-induced DNA damage, contributing to mutational burden that may promote malignant progression. We identify that fibrotic breast tumors display higher mutational burdens. Mechanistically, tissue tension increases epithelial STAT3 to drive chemokine-mediated macrophage recruitment. Stiffness promotes reactive oxygen species-induced lipid peroxidation in recruited macrophages, generating aldehydes that damage DNA and enhance progression. Notably, high mammographically dense breast tissues-associated with increased Cancer risk-are stiffer and inflamed and display elevated lipid aldehydes and DNA damage. This work links fibrosis and inflammation to tension-mediated Cancer initiation and progression.

Keywords

DNA damage; breast cancer; extracellular matrix; inflammation; lipid peroxidation; macrophages; stromal stiffness; tissue fibrosis; tumor microenvironment.

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