journal contribution posted on 2023-05-01, 08:22 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 S6. Flow cytometry data for CSC stains. Cell type of interest is bolded in co-culture comparisons. A) Representative gating scheme for ALDH activity, CD24, and CD44 analyses. B-D) Flow cytometry data for MCF7 (B), T47D (C), and HCC1428 (HCC, D) cells in monoculture versus co-culture with MSCs stained for ALDH activity, CD24, and CD44. N > 10,000 cells.
National Cancer Institute (NCI)
United States Department of Health and Human ServicesFind out more...
W. M. Keck Foundation (WMKF)
Division of Grants and Agreements (DGA)
ARTICLE ABSTRACTCancer 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.