Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment
Neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) eliminates tumors in about 45% of patients. However, those with significant residual cancer face poor metastasis-free and overall survival rates. We previously identified that residual TNBC cells surviving NACT show elevated mitochondrial oxidative phosphorylation (OXPHOS), making this a critical therapeutic target. To understand this heightened dependency on mitochondrial metabolism, we investigated the underlying mechanisms. Mitochondria are dynamic organelles that constantly undergo fission and fusion to sustain their integrity and metabolic balance. The effects of mitochondrial structure on metabolic output vary depending on the context.
Several chemotherapy agents are commonly used in NACT for TNBC. Our comparison of mitochondrial responses to these agents revealed that DNA-damaging drugs led to increased mitochondrial elongation, higher mitochondrial content, enhanced glucose flux through the TCA cycle, and increased OXPHOS. In contrast, taxanes reduced mitochondrial elongation and OXPHOS. The impact of DNA-damaging chemotherapies on mitochondria depended on the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). Additionally, we observed elevated OXPHOS, increased OPA1 protein levels, and more mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Disrupting mitochondrial fusion and fission pharmacologically or genetically affected OXPHOS, indicating that elongated mitochondria promote OXPHOS in TNBC cells.
In TNBC cell lines and the in vivo PDX model of residual TNBC, we found that sequential treatment with DNA-damaging chemotherapy, which induces mitochondrial fusion and OXPHOS, followed by MYLS22, a specific OPA1 inhibitor, significantly reduced mitochondrial fusion and OXPHOS, and inhibited the regrowth of residual tumor cells. Our findings suggest that OPA1-mediated mitochondrial fusion enables TNBC cells to optimize OXPHOS, potentially providing a strategy to overcome the mitochondrial adaptations of chemoresistant TNBC.