Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability.
Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability.
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微流控肿瘤芯片模型研究肿瘤代谢脆弱性。
DOI：
10.3390/ijms21239075
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发表时间：
2020-11-28
影响因子：
5.6
通讯作者：
Beebe DJ
中科院分区：
文献类型：
--
作者：
Ayuso JM;Rehman S;Farooqui M;Virumbrales-Muñoz M;Setaluri V;Skala MC;Beebe DJ
肿瘤特异性代谢适应提供了一个有趣的治疗机会，选择性地摧毁癌细胞。然而，实体瘤也会在整个肿瘤块中呈现营养物质和废物的梯度，迫使肿瘤细胞根据周围微环境中的营养物质可用性来适应其代谢。因此，实体瘤在整个肿瘤块中显示出异质性代谢表型，这使得靶向所有存在的肿瘤群体的有效疗法的设计复杂化。在这项工作中，我们使用微流控装置来研究肿瘤代谢对几种代谢抑制剂的脆弱性。该微型装置包括一个中心腔室，用于在三维（3D）基质中培养肿瘤细胞，以及一个腔室侧面的管腔。这种设计在中央腔室中产生了不对称的营养分布，产生了细胞活力的梯度。结果显示，位于营养丰富的环境中的肿瘤细胞对靶向糖酵解、脂肪酸氧化或氧化磷酸化的代谢抑制剂的敏感性很低或没有。相反，当模型内的细胞密度增加时，营养供应受到影响，这些代谢抑制剂的加入破坏了细胞的氧化还原平衡，导致肿瘤细胞死亡。
Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death.
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