美国纽约大学医学中心Alec C. Kimmelman和美国达纳-法伯癌症研究所Andrew J. Aguirre研究团队合作取得最新进展。他们利用功能基因组学确定了胰腺癌中的代谢脆弱性。相关论文发表在2020年11月4日出版的《细胞-代谢》杂志上。

为了系统地研究胰腺导管腺癌（PDA）中的代谢脆弱性，他们使用了体内和体外系统的并行CRISPR-Cas9筛选。这项工作揭示了体内代谢依赖性与体外代谢依赖性的惊人重叠。此外，他们发现细胞间的营养共享可以掩盖汇总筛选中的依赖性，突显了这种研究肿瘤代谢方法的局限性。

此外，尽管3D培养可能会更好地建模，并影响某些致癌信号通路的漏洞，但2D和3D培养之间的代谢依赖性相似。最后，他们的工作证明了遗传筛选方法可定义体内代谢依赖性和可能具有治疗作用的途径。

据了解，PDA是一种致命的癌症，其特征在于复杂的代谢适应，可在严重缺氧和营养受限的肿瘤微环境（TME）中促进生存。对细胞培养中的微环境影响进行建模一直具有挑战性，并且技术局限性阻碍了体内肿瘤特异性代谢的全面研究。

附：英文原文

Title: Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer

Author: Douglas E. Biancur, Kevin S. Kapner, Keisuke Yamamoto, Robert S. Banh, Jasper E. Neggers, Albert S.W. Sohn, Warren Wu, Robert T. Manguso, Adam Brown, David E. Root, Andrew J. Aguirre, Alec C. Kimmelman

Issue&Volume: 2020-11-04

Abstract: Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer characterized by complexmetabolic adaptations that promote survival in a severely hypoxic and nutrient-limitedtumor microenvironment (TME). Modeling microenvironmental influences in cell culturehas been challenging, and technical limitations have hampered the comprehensive studyof tumor-specific metabolism in vivo. To systematically interrogate metabolic vulnerabilities in PDA, we employed parallelCRISPR-Cas9 screens using in vivo and in vitro systems. This work revealed striking overlap of in vivo metabolic dependencies with those in vitro. Moreover, we identified that intercellular nutrient sharing can mask dependenciesin pooled screens, highlighting a limitation of this approach to study tumor metabolism.Furthermore, metabolic dependencies were similar between 2D and 3D culture, although3D culture may better model vulnerabilities that influence certain oncogenic signalingpathways. Lastly, our work demonstrates the power of genetic screening approachesto define in vivo metabolic dependencies and pathways that may have therapeutic utility.

DOI: 10.1016/j.cmet.2020.10.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30551-9