Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, United States of America.
Norris Comprehensive Cancer Center, University of Southern California, University of Southern California, Los Angeles, California, United States of America.
PLoS Comput Biol. 2021 Apr 19;17(4):e1008942. doi: 10.1371/journal.pcbi.1008942. eCollection 2021 Apr.
The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such that cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.
癌细胞的代谢重编程产生了可治疗靶向的代谢脆弱性。然而，我们对代谢依赖性以及在癌细胞中产生这些脆弱性的途径串扰的理解仍不完整。在这里，我们通过整合数百种癌细胞系的基因表达数据与遗传功能丧失和药理学筛选数据，在途径水平而非单个基因水平上确定了代谢脆弱性。这种方法表明，代谢途径依赖性具有高度的特定于上下文的特点，只有当另一种代谢途径的活性改变时，癌细胞才容易受到一种代谢途径的抑制。值得注意的是，我们还发现没有单一的代谢途径是普遍必需的，这表明癌细胞并不总是依赖任何代谢途径。此外，我们还证实细胞培养基是分析代谢途径脆弱性的主要混杂因素。尽管如此，我们还是发现代谢途径活性与临床批准药物的敏感性之间存在稳健的关联，这些关联独立于细胞培养基。最后，我们使用药理学和遗传依赖性数据的并行整合来自信地识别代谢途径脆弱性。总之，这项研究全面描述了癌细胞系中代谢途径脆弱性的景观。
