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

Abstract

<div>Abstract<p>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<sup>+</sup>) 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<sup>+</sup> 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<sup>+</sup> breast cancer and overcome resistance to standard clinical therapies.</p>Implications:<p>This study reveals how MSCs reprogram metabolism of ER<sup>+</sup> breast cancer cells and point to MCT4 as potential therapeutic target to overcome resistance to antiestrogen drugs.</p></div>

A Multiomic Analysis Reveals How Breast Cancers Disseminated to the Bone Marrow Acquire Aggressive Phenotypes through Tumor-Stroma Tunnels

“…Prior to injection, we verified equal numbers of viable cells based on bioluminescence imaging of aliquots of each cell type. To generate systemic metastases, we injected 1 x 10 5 MCF7-CBG or MCF7-CBG-GIV cells into the left ventricle of 7–10- week-old female NSG mice (7-8 mice per group) (The Jackson Lab, Bar Harbor, ME, USA) as described previously by our lab (89).…”

“…For co-culture assays, we seeded 12,000 total cells per cm 2 in 35 mm dishes with a ratio of 1:9 ER+ breast cancer cells to MSCs. One day after seeding, we washed cells once with phosphate buffered saline (PBS) and then changed medium to phenol-red free DMEM (#A14430-01, Gibco), supplemented with 1% FBS, 1% P/S, 1% Glutamax, 1% sodium pyruvate, 10 nM β-estradiol (#E2758, Sigma-Aldrich, Millipore Sigma, Saint Louis, MO, USA), and 5 mM glucose (89). We cultured cells in low serum (1%), low glucose (4 mM), and 10 nM estrogen (LG/LF) medium for 3 days before analyzing experimental endpoints.…”

“…We resuspended cells at 1 x 10 We performed bioluminescence imaging (IVIS Spectrum, Perkin Elmer) on mice at days indicated in the figure legend. At the end of the study, we measured metastases in defined organs by ex vivo bioluminescence imaging as we reported previously (89). We quantified total bioluminescence signal above background using Living Image software.…”