Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Syst. 2019 Sep 25;9(3):258-270.e6. doi: 10.1016/j.cels.2019.07.006. Epub 2019 Sep 11.
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 non-canonical 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.
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 致癌性的下游途径的能力受到对调节激活的 K-RAS 信号输出的上下文线索理解不完整的限制。我们对表达野生型或突变 Kras 的小鼠组织进行了质谱分析，以确定组织背景和遗传背景如何调节致癌信号。突变的 Kras 以特定于上下文的方式极大地改变了癌前和肿瘤结肠和胰腺的蛋白质组和磷酸蛋白质组。我们开发了一种方法，通过来自人类癌症的数据对小鼠网络进行统计学上的拟人化，并确定了人类化 CRC 和 PDAC 网络中与突变 KRAS 具有合成致死性的基因。我们的研究表明致癌信号的上下文依赖性可塑性，确定了 KRAS 调节信号网络内 KRAS 致癌性的非典型介质，并展示了如何对小鼠和人类数据集进行统计整合可以揭示跨物种的治疗见解。
