Imaging Sensitivity of Quiescent Cancer Cells to Metabolic Perturbations in Bone Marrow Spheroids.
Imaging Sensitivity of Quiescent Cancer Cells to Metabolic Perturbations in Bone Marrow Spheroids.
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DOI：
10.18383/j.tom.2016.00157
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Luker GD
中科院分区：
文献类型：
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作者：
Cavnar SP;Xiao A;Gibbons AE;Rickelmann AD;Neely T;Luker KE;Takayama S;Luker GD
来自乳腺癌以及其他常见癌症（如前列腺癌和黑色素瘤）的恶性细胞可能在骨髓中持续存在，作为静止的非分裂细胞，在恢复增殖以引起复发性疾病之前保持存活数年甚至数十年。这种现象在临床上被称为肿瘤休眠，给乳腺癌患者的治疗带来了巨大的挑战。静止的肿瘤细胞抵抗主要靶向增殖细胞的化疗药物，限制了新辅助和辅助治疗的成功。我们最近开发了一个骨髓中静止乳腺癌细胞的三维球体模型，用于机制和药物测试研究。我们将该模型与光学成像方法结合起来，用于无标记检测细胞，优先使用糖酵解与氧化代谢来研究与不同骨髓基质细胞和乳腺癌细胞共培养球体的代谢状态。通过成像和生化分析，我们确定了控制共培养乳腺癌细胞代谢状态和灵活性的骨髓基质细胞的不同代谢状态。我们测试了代谢应激和特定代谢途径的靶向抑制，以确定从骨髓环境中优先消除静止乳腺癌细胞的方法。这些研究建立了一种综合成像方法来分析复杂组织环境中的代谢，以确定新的代谢靶向癌症疗法。
Malignant cells from breast cancer, as well as other common cancers such as prostate and melanoma, may persist in bone marrow as quiescent, nondividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neoadjuvant and adjuvant therapies. We recently developed a 3-dimensional spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells, preferentially using glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically targeted cancer therapies.