Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan.
Mol Cancer Res. 2023 May 1;21(5):458-471. doi: 10.1158/1541-7786.MCR-22-0451.
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.
癌细胞通过代谢可塑性重新编程能量代谢，根据治疗或微环境变化调整产生 ATP 的途径。这种适应使癌细胞能够抵抗标准疗法。我们采用雌激素受体阳性（ER+）乳腺癌和间充质干细胞（MSC）的共培养模型来模拟癌细胞与基质微环境的相互作用。使用用于细胞代谢的单细胞内源性和工程生物传感器，与 MSC 的共培养增加了氧化磷酸化、细胞内 ATP 以及癌细胞对标准疗法的抵抗力。共培养的癌细胞增加了乳酸转运蛋白 MCT4，并对 MCT1/4 抑制剂苦马豆素敏感。将苦马豆素与氟维司群（一种选择性雌激素受体降解药物）联合使用，克服了 ER+乳腺癌细胞与 MSC 共培养时的耐药性。抗雌激素治疗增加了代谢可塑性并维持了细胞内 ATP 水平，而 MCT1/4 抑制成功限制了代谢转变并降低了 ATP 水平。此外，MCT1/4 抑制降低了与抗雌激素治疗相比的异质代谢治疗反应。这些数据确立了 MSC 作为癌细胞代谢可塑性的介质，并表明代谢干预是治疗 ER+乳腺癌和克服对标准临床疗法的耐药性的有前途的策略。
这项研究揭示了 MSC 如何重新编程 ER+乳腺癌细胞的代谢，并指出 MCT4 可能是克服抗雌激素药物耐药性的潜在治疗靶点。
