POLG mediates CAF-stimulated TNBC cell metastasis by utilizing internal and exosome-derived external mtDNA to increase oxidative phosphorylation

Abstract The challenge for triple-negative breast cancer (TNBC) treatment stems from its highly aggressive metastatic features. Mitochondrial metabolism has emerged as the dominant metabolic phenotype in TNBC cells during metastatic progression and is an attractive targetable biological process. Cancer-associated fibroblasts (CAFs), the main components of the tumour microenvironment, increase mitochondrial metabolism in TNBC cells; however, the underlying mechanisms remain unclear. Here, we identified DNA polymerase (POLG), a critical enzyme for mitochondrial DNA (mtDNA) replication and translation, as a novel promoter of TNBC metastasis. In TNBC cells, CAF-stimulated expression and enzymatic activity of POLG and oxidative phosphorylation (OXPHOS) were found to be increased. Increased levels of POLG utilize both internal and CAF-exosome-derived external mtDNA to improve the quantity and functionality of OXPHOS complexes, facilitating respiration and ATP production, which in turn promotes TNBC cell metastasis. Furthermore, high POLG expression indicates an unfavourable prognosis and an increased metastatic tendency in TNBC patients compared with individuals with other breast cancer subtypes. The transcription factor oestrogen-related receptor α (ERRα) and its coactivator peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) cooperate to transactivate POLG in CAF-stimulated TNBC cells. Knockdown or pharmacological inhibition of POLG expression significantly reduced CAF-stimulated TNBC metastasis both in vivo and in vitro. Our investigation suggests that targeting POLG disrupts CAF-stimulated metabolic reprogramming towards OXPHOS in TNBC cells, thereby suppressing metastasis. These findings highlight a potential therapeutic strategy for the treatment of TNBC.