Radiation-Induced Autophagy Regulates the Fibroblast Mitochondrial Stress Response and Crosstalk with Triple-Negative Breast Cancer Cells

Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which includes radiation therapy (RT). Tumor cells thought to be involved in recurrence survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo a mitochondrial stress response that is regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. This stress response in fibroblasts induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals how a metabolic stress response in irradiated fibroblasts and crosstalk with TNBC cells leads to a microenvironment conducive to recurrence. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/492249v3_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@181680aorg.highwire.dtl.DTLVardef@d58a1forg.highwire.dtl.DTLVardef@15f04eforg.highwire.dtl.DTLVardef@13cf5f9_HPS_FORMAT_FIGEXP M_FIG C_FIG