In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth
In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth
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DOI：
10.1101/2021.07.05.449722
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发表时间：
2021-07
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通讯作者：
Nicholas T Younger;M. L. Wilson;E. Jarman;A. Meynert;G. Grimes;Konstantinos Gournopanos;S. Waddell;P. Tennant;D. Wilson;R. Guest;S. Wigmore;J. Acosta;T. Kendall;Martin S. Taylor;D. Sproul;P. Mill;L. Boulter
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作者：
Nicholas T Younger;M. L. Wilson;E. Jarman;A. Meynert;G. Grimes;Konstantinos Gournopanos;S. Waddell;P. Tennant;D. Wilson;R. Guest;S. Wigmore;J. Acosta;T. Kendall;Martin S. Taylor;D. Sproul;P. Mill;L. Boulter
肝内胆管细胞癌（ICC）是一种侵袭性和致命的恶性肿瘤的胆管内的肝脏，其特点是高水平的遗传异质性。在这种遗传变异性的背景下，确定哪些致癌突变驱动ICC生长一直是困难的，并且开发患者分层和靶向治疗的模式仍然具有挑战性。因此，自20世纪70年代末以来，ICC诊断后的生存率一直保持不变，而ICC的发病率则有所增加。在这里，我们进行了第一个功能性体内研究，通过模拟罕见突变与更常见的驱动基因之间的相互作用，研究遗传异质性在驱动ICC中的作用。通过利用人类ICC测序数据对小鼠的遗传异质性进行分层和建模，我们发现了许多新的肿瘤抑制因子，这些抑制因子在丢失时与RAS癌蛋白合作驱动ICC生长。在这项研究中，我们特别关注一组与KRAS相互作用以启动侵袭性肉瘤型ICC的驱动突变。我们发现，这种癌症的肿瘤生长依赖于Wnt和PI3K信号传导来驱动增殖和抑制凋亡。最后，我们证明了Wnt和PI3K在体内的药理学共抑制实质上阻碍了ICC的生长，无论突变概况如何。因此，Wnt和PI3K活性应被视为一种特征，通过该特征可以对患者进行治疗分层，并且这些途径的抑制剂应被征收作为诊断为ICC的患者的治疗。
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy of the bile ducts within the liver characterised 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. As a result, survival rates following a diagnosis with ICC have remained static since the late 1970s, whilst incidence of ICC has increased. Here, we performed the first functional in vivo study into the role that genetic heterogeneity plays in drivinga ICC via modelling of interactions between rare mutations with more common driver genes. By leveraging human ICC sequencing data to stratify and then model genetic heterogeneity in the mouse, we uncovered numerous novel tumour suppressors which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. In this study, we specifically focus on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC. We show that tumour growth of this cancer relies on both Wnt and PI3K signalling to drive proliferation and suppress apoptosis. Finally, we demonstrate that pharmacological co-inhibition of Wnt and PI3K in vivo substantially impedes the growth of ICC, regardless of mutational profile. As such, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment and inhibitors of these pathways should be levied as a treatment for patients diagnosed with ICC.