3D EM uncovers mitochondrial network remodeling in residual triple negative breast cancer after conventional chemotherapy treatments.

Mitochondria are hubs of metabolism and signaling. We previously demonstrated the importance of mitochondrial structure and function in chemotherapy-refractory triple-negative breast cancer (TNBC). Herein, we present the first 3D analysis of mitochondrial networks in human tumor tissues. Using serial block face scanning electron microscopy, we reconstructed 3,750 mitochondria and 800 lipid droplets (LDs) in naive and residual tumors persisting after conventional chemotherapies in two orthotopic patient-derived xenografts (PDX). Chemotherapies administered as monotherapy or in combination produced residual tumors that harbored mitochondria with significantly increased areas, volumes, and perimeters. We observed substantial reduction of mitochondrial intratumor heterogeneity following all treatments. Further, mitochondrial complexity was significantly elevated after single-agent treatments in one model, but was reduced in the other PDX model. Mitochondria-LD significantly increased contacts in residual tumors, congruent with our previous studies providing evidence for rewiring of lipid metabolism in residual TNBC. These results highlight the potential for structure-based monitoring of chemotherapy-induced metabolic rewiring in TNBC.