Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor-Positive Breast Cancer

Cancer cells reprogram energy metabolism through metabolic plasticity, adapting ATP-generating pathways in response to treatment or microenvironmental changes. Such adaptations enable cancer cells to resist standard therapy. We employed a coculture model of estrogen receptor-positive (ER+) breast cancer and mesenchymal stem cells (MSC) to model interactions of cancer cells with stromal microenvironments. Using single-cell endogenous and engineered biosensors for cellular metabolism, coculture with MSCs increased oxidative phosphorylation, intra-cellular ATP, and resistance of cancer cells to standard therapies. Cocultured cancer cells had increased MCT4, a lactate trans-porter, and were sensitive to the MCT1/4 inhibitor syrosingo-pine. Combining syrosingopine with fulvestrant, a selective estrogen receptor degrading drug, overcame resistance of ER+ breast cancer cells in coculture with MSCs. Treatment with antiestrogenic therapy increased metabolic plasticity and main -ta ined intracellular ATP levels, while MCT1/4 inhibition suc-cessfully limited metabolic transitions and decreased ATP levels. Furthermore, MCT1/4 inhibition decreased heterogenous meta-bolic treatment responses versus antiestrogenic therapy. These data establish MSCs as a mediator of cancer cell metabolic plasticity and suggest metabolic interventions as a promising strategy to treat ER+ breast cancer and overcome resistance to standard clinical therapies. Implications: This study reveals how MSCs reprogram metabolism of ER+ breast cancer cells and point to MCT4 as potential thera-peutic target to overcome resistance to antiestrogen drugs.

Automated summary

Cancer cells adapt their energy metabolism to resist therapy through metabolic plasticity. In a coculture model of ER+ breast cancer and MSCs, it was found that coculturing with MSCs increased oxidative phosphorylation and ATP levels, leading to resistance to standard therapies. This resistance was overcome by inhibiting MCT1/4 and combining it with fulvestrant, suggesting metabolic interventions as potential strategies to overcome resistance in ER+ breast cancer.