基于单细胞RNA-seq数据识别驱动癌症细胞获得转移潜能的关键因子

Metastases account for the great majority of cancer-associated deaths, therefore, it is crucial to dissect the molecular mechanism. A large number of studies have shown that cancer cells can obtain metastatic potential and phenotype in early stage of cancer. However, little is known about its driver factors and the underlying molecular cascades. Notably, single-cell sequencing technique can characterize the molecule profiles, which provides powerful technical support for solving this problem. Thus, this project focuses on the single-cell RNA-seq data and constructs single-cell transcriptome profile of multiple cancers. We identify cell subpopulations with metastatic potential through integrating multiple data resources. Based on reconstructed trajectory, pseudotime and state of cancer cells and combining single-cell transcriptional regulatory network, we dynamically identify the key driver factors and molecular cascades in the process that cancer cells obtain metastatic potential. Besides, we use cellular functional experiments and clinical samples to validate the biological functions of key driver factors. Finally, we develop a comprehensive bioinformatics platform, which can analyze single-cell data of cancer. Our results can elucidate the molecular mechanism of the early metastasis, enhance our understanding of cancer metastasis and tumor evolution, and provide new strategies and targets for the prevention and treatment of metastatic tumors.

转移是绝大多数癌症引起死亡的主要原因，解析其分子机制至关重要。大量的研究表明癌症细胞能够在癌症早期就获得转移潜能和表型，但对于驱动该事件的关键因子及分子级联知之甚少。近年来，单细胞测序技术迅速发展，能够刻画单个细胞分子图谱，为解决此问题提供了强力的技术支持。因此，本项目以单细胞RNA-seq数据为核心，构建多种癌症的单细胞转录组图谱，整合多种数据资源识别具有转移潜能的细胞亚群；基于重构的癌症细胞进展轨迹、时序和状态预测，融合单细胞转录调控网络，动态识别在癌症细胞获得转移潜能过程中的关键驱动因子和分子级联事件，并利用细胞功能学实验和临床样本进行验证，最终开发癌症单细胞数据综合分析平台。本项目旨在阐明驱动癌症早期转移的分子机制，加深对于癌症转移和肿瘤进化的理解，为预防和治疗转移性肿瘤提供新的策略和分子靶标。

癌症的侵袭转移是患者致死的主要原因，为临床的癌症治疗提出巨大挑战，然而相关研究成果仍未获得良好收益。因此，深入探究癌症细胞侵袭转移的分子机制及关键驱动因子至关重要。本项目以单细胞RNA-seq数据为核心，绘制多种癌症类型的单细胞转录组图谱，开发新颖算法和优化资源策略，识别单细胞水平下具有特异表达模式的基因，探究其在肿瘤起始和侵袭中的潜在作用；同时，我们将轨迹构建方法引入癌症细胞进展研究中，构建并确定胶质母细胞瘤从干性状态转变至具备侵袭潜能状态的进展路径，进而识别参与癌症细胞获得侵袭转移能力的关键调控因子，并通过实验完成验证；进一步，我们整合癌症转录组和基因组数据，分别通过构建拷贝数改变影响的竞争性内源RNA失调网络和gene-hallmark网络，挖掘影响癌症进展和临床表型的关键基因以及驱动基因。项目开展的系列工作，加深了对癌症细胞侵袭转移机制的理解，为临床转移性肿瘤的预防和治疗提供理论依据，为抗转移药物的开发提供分子靶标。