癌症转移单细胞转录谱分析揭示介导转移潜能的关键lncRNA

Metastases are the major cause of cancer-related deaths. Dsepite progression on understanding of cancer metastasis machanisms, treatment for metastatic cancer is still a tough problem. Strong expression specificity and wide regulation of lncRNAs make them ideal markers for diagnosis and prognosis, and candidate therapeutic targets. Therefore, precisely characterizing key lncRNAs playing critical roles in cancer metastasis cascade become an urgent topic, and it can be facilitated by recent advances of single-cell technologies. In this study, we integrate single-cell transcriptomic profiles of primary and metastatic cancer to establish a scoring system to quantify cancer metastasis state. Combing the scoring system with cell clustering algorithm, cell subgroups with metastastic potential are identified in the primary cancer. Leveraging co-expression network analysis, we construct metastastic potential-related modules of lncRNAs and PCGs. Among these modules, we screen key lncRNAs mediating metastatic potential and validate their functions experimentally. Finally, an integrative bioinformatic platform for analysing metastatic potential-mediating key lncRNAs is developed. Implementation of this work will provide valuable tools for studies on cancer metastasis mechanisms, and pave the way to early diagnosis and treatment of cancer metastasis.

癌症转移一直是癌症死亡的最主要诱因，尽管多年来对于癌症转移机制的研究取得了一定成效，然而对于转移癌症的治疗几乎没有推动。lncRNA强烈的表达特异性及广泛的基因调控作用使其成为理想的诊断、预后标记物及潜在的治疗靶点。因此，精准地刻画在癌症转移过程中发挥重要介导作用的关键lncRNA成为一项亟需解决的课题，而单细胞测序技术的飞速发展为推动这一进程提供了强有力的工具。本项目拟整合原发与转移癌症单细胞转录组数据，构建癌症转移状态打分模型，量化癌症细胞的转移状态；进一步结合细胞聚类方法识别原发癌中具有转移潜能的细胞群体；通过共表达网络分析，构建转移潜能相关的lncRNA与PCG共表达模块，筛选出介导癌症转移潜能的关键lncRNA，并利用生物学实验进行验证；最后，开发癌症转移潜能关键介导lncRNA分析平台，为癌症转移机制研究提供新手段，为转移的早期诊断、治疗提供新策略。

本项目以癌症组织与单细胞转录组数据为基石，运用生物信息学方法筛选介导癌症发育、侵袭转移与预后的关键lncRNA，为癌症的预防和治疗提供新策略。在该课题研究过程中，我们通过整合lncRNA表达谱、基因表达谱、miRNA表达谱与遗传改变谱，构建遗传改变诱导的失调ceRNA网络，识别在癌症中发挥关键作用的lncRNA/基因，并进行泛癌分析来探索其在多种癌症类型中的共性与特异性。进一步以lncRNA为主体，构建基于lncRNA的乳腺癌预后预测模型，探究lncRNA对于癌症预后的影响及潜在的临床应用价值。此外，我们基于单细胞转录组数据，利用共表达网络分析方法，筛选与胶质母细胞瘤侵袭相关的lncRNA，验证了lncRNA对于癌症侵袭转移的贡献。另外，我们基于单细胞转录组数据深刻剖析了癌症中微环境T细胞的异质性功能状态，并刻画其在癌症中失调的调控机制。本研究通过整合组织层面与单细胞层面的转录组数据识别驱动癌症及转移的关键因子的方法和策略对于理解癌症的发病机理增添新的线索，为癌症的诊断与治疗靶点开发提供新的角度。