Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation
Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation
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DOI：
10.1016/j.cels.2019.07.006
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发表时间：
2019-09-25
期刊：
影响因子：
9.3
通讯作者：
Haigis, Kevin M.
中科院分区：
文献类型：
--
作者：
Brubaker, Douglas K.;Paulo, Joao A.;Haigis, Kevin M.
KRAS突变的最高频率发生在结直肠癌（CRC）和胰腺导管腺癌（PDAC）中。靶向介导KRAS致癌性的下游通路的能力受到对调节活化K-RAS信号输出的上下文线索的不完全理解的限制。我们对表达野生型或突变型Kras的小鼠组织进行质谱分析，以确定组织环境和遗传背景如何调节致癌信号传导。突变Kras以特定的方式显著改变肿瘤前和肿瘤结肠和胰腺的蛋白质组和磷蛋白质组。我们开发了一种方法，利用来自人类癌症的数据对小鼠网络进行统计人源化，并在人源化的CRC和PDAC网络中鉴定出与突变KRAS合成致死的基因。我们的研究证明了致癌信号的环境依赖性可塑性，在KRAS调节的信号网络中确定了KRAS致癌性的非规范介质，并证明了小鼠和人类数据集的统计整合如何揭示跨物种治疗见解。
The highest frequencies of KRAS mutations occur in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). The ability to target downstream pathways mediating KRAS oncogenicity is limited by an incomplete understanding of the contextual cues modulating the signaling output of activated K-RAS. We performed mass spectrometry on mouse tissues expressing wild-type or mutant Kras to determine how tissue context and genetic background modulate oncogenic signaling. Mutant Kras dramatically altered the proteomes and phosphoproteomes of preneoplastic and neoplastic colons and pancreases in a context-specific manner. We developed an approach to statistically humanize the mouse networks with data from human cancer and identified genes within the humanized CRC and PDAC networks synthetically lethal with mutant KRAS. Our studies demonstrate the context-dependent plasticity of oncogenic signaling, identify noncanonical mediators of KRAS oncogenicity within the KRAS-regulated signaling network, and demonstrate how statistical integration of mouse and human datasets can reveal cross-species therapeutic insights.