No 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.

Radiation therapy (RT) is essential for triple negative breast cancer (TNBC) treatment. However, patients with TNBC continue to experience recurrence after RT. The alteration of extracellular matrix (ECM) of healthy breast tissue induced by radiation and its role on tumor recurrence are still unknown. In this study, we evaluated the structure, molecular composition, and mechanical properties of irradiated murine mammary fat pads (MFPs) and developed ECM hydrogels from decellularized tissues to assess the effects of RT-induced ECM changes on breast cancer cell behavior. Irradiated MFPs were characterized by increased ECM deposition and fiber density compared to unirradiated controls, which may provide a platform for cell invasion and proliferation. Alterations in irradiated ECM components including collagen I, IV, VI, and fibronectin were observed. TNBC cell proliferation was enhanced in irradiated hydrogels. Encapsulated TNBC cell morphology analysis indicated an increase in invasive capacity within irradiated ECM hydrogels. In addition, TNBC cells co-cultured with macrophages in irradiated ECM hydrogels exhibited further increases in cell proliferation. Our study establishes that the ECM in the irradiated microenvironment promotes TNBC invasion and proliferation that is enhanced in the presence of macrophages. This work represents an important step toward elucidating how changes in the ECM after RT contribute to breast cancer recurrence.