Radiation-Induced Metabolic Reprogramming of Fibroblasts Regulates the Breast Cancer Microenvironment

Abstract

Triple negative breast cancer (TNBC) patients continue to have high recurrence rates despite current treatment modalities, including radiation therapy (RT). Radiation-resistant TNBC cells and circulating tumor cells thought to be involved in recurrence survive in part due to changes in their metabolic profiles. These tumor cells interact with radiation-damaged stromal cells such as fibroblasts following treatment. How fibroblasts metabolically respond to RT and metabolically crosstalk with TNBC cells is poorly understood. In this study, we identified that radiation-damaged fibroblasts accumulate lipids up to 7-days following treatment due to increased autophagic flux. This lipid accumulation and autophagy allows fibroblasts to maintain increased fatty acid oxidation, overall mitochondrial respiration, and aerobic glycolysis rates. TNBC cells responded by decreasing autophagy and increasing ATP-linked respiration and migration rates. Our work highlights how metabolic crosstalk between radiation-damaged fibroblasts and TNBC cells leads to a microenvironment conducive to recurrence.