In Vivo Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma.
In Vivo Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma.
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DOI：
10.1158/0008-5472.can-21-2556
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发表时间：
2022-04-15
期刊：
影响因子：
11.2
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中科院分区：
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这项研究表明，尽管存在显著的遗传异质性，肝内胆管癌依赖于有限数量的信号通路生长，这表明在所有患者中存在共同的治疗脆弱性。肝内胆管癌（ICC）是肝脏内胆管的侵袭性恶性肿瘤，具有高度的遗传异质性。在这种遗传变异的背景下，确定哪些致癌突变驱动ICC生长一直很困难，并且开发患者分层和靶向治疗模式仍然具有挑战性。在这里，我们模拟了罕见突变与更常见驱动基因之间的相互作用，并将患者数据的计算机分析与高度多路的体内CRISPR-spCas9筛选相结合，对遗传异质性在驱动ICC中的作用进行了功能性体内研究。新的肿瘤抑制因子被发现，当失去时，它们与RAS癌蛋白合作驱动ICC生长。关注一组与KRAS相互作用启动侵袭性肉瘤型ICC的驱动突变，揭示了肿瘤生长依赖于Wnt和PI3K信号。无论突变谱如何，体内Wnt和PI3K的药理学共抑制都会阻碍ICC的生长。因此，Wnt和PI3K活性应被视为一个标志，通过该标志可以对患者进行分层治疗，而不依赖于肿瘤基因型，并且应该使用这些途径的抑制剂来治疗ICC。这项研究表明，尽管存在显著的遗传异质性，肝内胆管癌依赖于有限数量的信号通路生长，这表明在所有患者中存在共同的治疗脆弱性。
This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC. This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.