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沿着catabolic-anabolic轴的癌细胞代谢的计算建模
Javier Villela-Castrejon1,2, Herbert Levine3,4, Benny A Kaipparettu5,6
1Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA.
癌细胞表现出不同的代谢表型,利用葡萄糖,脂肪酸和谷氨酸. 癌瘤中的混合代谢状态与较差的生存率相关,突出了代谢可塑性作为治疗点.
科学领域:
- 在瘤学瘤学.
- 代谢工程是代谢工程.
- 系统生物学 系统生物学
背景情况:
- 细胞代谢异常,包括有氧糖解和线粒体呼吸,是癌症的一个基本特征.
- 癌细胞整合各种代谢途径和基质 (葡萄糖,脂肪酸,谷氨酸) 来促进其生长和生存的确切机制仍然不完全理解.
研究的目的:
- 通过将关键基因调节剂 (AMPK,HIF-1,MYC) 与主要代谢基质集成,开发癌症代谢的表型模型.
- 定义和表征癌细胞中不同的代谢表型.
- 调查代谢表型与患者生存结果之间的关联.
主要方法:
- 制定一种表型模型,将基因调节剂与代谢基质结合起来.
- 开发基于基因表达的评分指标,以量化代谢途径活性.
- 从癌症基因组图谱 (TCGA) 瘤样本中分析RNA测序数据,以验证模型和表型.
主要成果:
- 该模型预测了四种不同的癌症代谢表型:氧化性 (O),还原性 (W),混合性 katabolic/anabolic (W/O) 和胺-氧化性 (Q).
- 基因表达分析验证了模型的预测,将特定的基因活动与代谢途径和表型联系起来.
- 与其他表型相比,具有混合代谢表型 (W/O和Q) 的癌瘤样本显示出明显较差的生存结果.
结论:
- 一个新的数学模型和评分系统有效量化癌症代谢表型及其相关的基因代谢途径活动.
- 癌细胞表现出显著的代谢可塑性,采用不同的表型来满足生物能和生物合成需求.
- 癌症中的混合代谢状态与预后不佳有关,这表明向代谢可塑性可能是一个有前途的治疗策略.
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