The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3’ UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1+PD-1+CD8+ cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients.

中文翻译：

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用于识别生物靶点以帮助诊断和治疗结直肠癌患者肝转移的多维推荐框架


了解肿瘤转移的分子机制和确定癌症治疗的关键生物标志物的重要性日益增加。单组学分析受制于其对单个生物层的关注，无法完全阐明肿瘤分子谱的复杂性，因此可能会忽视关键的分子靶标。针对这一限制，我们开发了一个锚定在多组学知识图谱中的多目标推荐系统 （RJH-Metastasis 1.0），以整合基因组、转录组和蛋白质组数据以及确凿的文献证据，然后对肝转移结直肠癌 （CRCLM） 进行了综合分析。本系统共推荐了 25 个与 CRCLM 显著相关的关键基因，并进一步突出了 GNB1 、 GATAD2A 、 GBP2 、 MACROD1 和 EIF5B。具体而言，GNB1 在 CRCLM 患者中表现出较少的突变，但 RNA 转录和蛋白表达升高。GNB1 在促进结肠癌细胞恶性行为中的作用通过体外和体内研究得到证实。GNB1 的异常表达可能受 METTL1 驱动的 m7G 修饰的调节。METTL1 敲除降低了 GNB1 3' UTR 中的 m7G 修饰，增加了肝转移过程中的 mRNA 转录和翻译。此外，GNB1 通过促进记忆 B 细胞与 KLRB1+PD-1+CD8+ 细胞之间的 CLEC2C-KLRB1 相互作用诱导免疫抑制微环境的形成。GNB1 表达与 PD-1 抗体治疗在 CRCLM 患者中的疗效显著相关。 综上所述，我们的推荐系统可用于有效探索结直肠癌中的关键分子，其中 GNB1 被确定为结直肠癌患者的关键 CRCLM 启动子和免疫治疗生物标志物。