American Association for Cancer Research
mcr-22-0451_figure_s5_suppsf5.pdf (4.52 MB)

Figure S5 from Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor–Positive Breast Cancer

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journal contribution
posted on 2023-04-03, 20:21 authored by Johanna M. Buschhaus, Shrila Rajendran, Siyi Chen, Bryan L. Wharram, Avinash S. Bevoor, Alyssa C. Cutter, Brock A. Humphries, Tanner H. Robison, Alex P. Farfel, Gary D. Luker

Figure S5. Representative images of glucose and ATP FRET reporters in MSCs. Pseudocolor scale depicts high (red) and low (blue) CFP lifetime. Scale bar = 50 µm. Representative images of intracellular glucose (A) and ATP (B) in HS5 MSCs when in co-culture with ER+ breast cancer cells. Cancer cells are unlabeled in pseudocolor images.



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, intracellular ATP, and resistance of cancer cells to standard therapies. Cocultured cancer cells had increased MCT4, a lactate transporter, and were sensitive to the MCT1/4 inhibitor syrosingopine. 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 maintained intracellular ATP levels, while MCT1/4 inhibition successfully limited metabolic transitions and decreased ATP levels. Furthermore, MCT1/4 inhibition decreased heterogenous metabolic 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. This study reveals how MSCs reprogram metabolism of ER+ breast cancer cells and point to MCT4 as potential therapeutic target to overcome resistance to antiestrogen drugs.

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