Synthetic lethality in the context of chromosome 8p deletion in liver cancer

肿瘤发生涉及癌基因激活和肿瘤抑制基因（TSG）丢失，导致细胞信号转导失调。这些改变被认为会产生癌细胞的依赖性。了解这些合成的致命相互作用将使我们能够特异性地治疗肿瘤，同时使非肿瘤细胞不受影响。染色体8p缺失是上皮性肿瘤中最常见的病变之一，如HCC和多个TSG已在该区域内报道。目前的合成致死相互作用的筛选是使用RNAi或化学化合物在肿瘤细胞系中进行的，将癌基因活化与正常细胞进行比较。尽管它们的技术创新和对我们理解Ras依赖性癌细胞的脆弱性的重要性，但由于它们的系统中缺乏相关的生理信号，这些筛选可能会低估靶点。因此，我想建立一个类似于染色体8p缺失的小鼠“马赛克”肝癌模型，以研究生理背景下的漏洞。靶向8p TSGs的短发夹RNA将使肝祖细胞（LPC）对恶性转化敏感并用作模型系统。这些LPC将用于通过应用靶向约1000个癌症信号传导基因的可调节RNAi来鉴定具有8 p缺失的肿瘤的体内合成致死相互作用，对于这些癌症信号传导基因，药理学抑制剂可用于将联合收割机遗传筛选与化合物验证相结合。随后，将用相应的抑制剂治疗肿瘤，以确认所鉴定基因的适用性。此外，将对8p缺失的人HCC细胞进行遗传学和免疫学测试，以确定其对这些基因抑制的敏感性。此外，潜在的信号通路将被描绘，以提高我们对肿瘤信号网络的理解。这项研究将使我们能够揭示8p依赖性肝肿瘤的脆弱性，帮助确定治疗HCC的新药物靶点。

Tumorigenesis involves oncogene activation and tumor suppressor gene (TSG) loss leading to dereg-ulation of cellular signaling. These alterations are thought to create dependencies of cancer cells. Knowledge of these synthetic lethal interactions will enable us to specifically treat tumors while leaving non-tumor cells unaffected. Chromosome 8p deletion is one of the most common lesions in epithelial tumors, such as HCC and multiple TSGs have been reported within this region. Current screens for synthetic lethal interactions were performed using RNAi or chemical compounds in tumor cell lines comparing oncogene activation to normal cells. Despite their technical innovation and importance for our understanding of vulnerabilities of Ras-dependent cancer cells, these screens might underestimate targets due to a lack of relevant physiological signaling in their systems. Therefore, I want to establish a mouse “mosaic” liver cancer model resembling chromosome 8p deletion to investigate vulnerabilities in a physiological context. Short hairpin RNAs targeting 8p TSGs will sensitize liver progenitor cells (LPCs) to malignant transformation and serve as model system. These LPCs will be used to identify synthetic lethal interactions of tumors with 8p deletions in vivo by applying regulateable RNAi targeting ~1000 cancer-signaling genes for which pharmacological inhibitors are available to combine genetic screening with compound validation. Subsequently, tumors will be treated with corresponding inhibitors to confirm applicability of the identified genes. In addition, human HCC cells with 8p deletions will be genetically and pharmacologically tested for their susceptibility to the inhibition of these genes. Furthermore, the underlying signaling pathways will be delineated to improve our understanding of tumor signaling networks. This study will enable us to reveal vulnerabilities of 8p-dependent liver tumors helping to identify novel drug targets for the treatment of HCC.