早期胃癌干细胞与巨噬细胞动态互作的分子功能可视化研究

Detection of early gastric cancer remains a major challenge in clinical settings in China, given that majority of gastric cancer patients are diagnosed at advanced stages, leading to ineffective treatment and poor prognosis. Thus, it is of high importance to further decipher the mechanisms underlying tumorigenesis of early gastric cancer. We have performed single cell transcriptome analysis of early gastric cancers and oberved an expansion of stem-like cells (CSCs) and profound infiltration of tumor-associated macrophages (TAM). By analyzing the significantly overexepressed genes in both CSCs and TAM, we have identified a panel of biomarkers that could be exploited for molecular imaging of the cells. In this proposal, we intend to isolate specific aptamers for specific targeting of CSCs and TAM. We will label the aptamers with new-generation quantum dots that were shown to be biologically stable and low toxic. Together, this project will not only develop novel molecular imaging techniques to visualize dynamic interactions between CSCs and TAM, but also provide cutting-edge tools to facilitate molecular diagnosis of early gastric cancer.

我国早期胃癌检出率低，大部分患者确诊时已是进展期，导致胃癌死亡率高、临床预后极差，亟需深入研究早期胃癌的调控机理，寻找其生物标志物。我们采用单细胞转录组测序，发现早期胃癌实质成分中肿瘤干细胞亚群显著扩增，肿瘤微环境中大量巨噬细胞浸润；分析二者关键分子谱征，揭示了众多针对早癌干细胞和巨噬细胞的分子成像靶向单元。本项目拟筛选靶向早期胃癌干细胞与巨噬细胞的核酸适配体，通过分子标记的新型低毒、高稳定性量子点荧光材料，实现对早期胃癌的在体、实时识别，以可视化方式呈现早癌干细胞与巨噬细胞动态互作，揭示免疫微环境驱动早期胃癌发生的分子新机理，建立高效的图像诊断模型，以开发早期胃癌的可视化分子诊断新方法。

我国早期胃癌检出率低，大部分患者确诊时已是进展期，导致胃癌死亡率高、临床预后极差，亟需深入研究胃癌调控新机理，寻找早诊早治和精准诊疗新策略。我们采用单细胞转录组测序，发现早期胃癌实质成分中肿瘤干细胞亚群显著扩增，肿瘤微环境中大量巨噬细胞浸润；分析二者关键分子谱征，揭示了众多针对早癌干细胞和巨噬细胞的分子成像靶向单元。进一步发现增强子表观重塑驱动早期胃癌进展的关键分子机制，CTNNB1在早期胃癌进展过程中预激活，其增强子可能受HOXA11调控，进而参与早癌进展恶变，为分子功能可视化提供分子靶标。本项目联合染色质开放性和组蛋白修饰组学技术，发现新的胃癌染色质可及性分子分型，即C1、C2、C3三种亚型，其中C3组可能为“恶性亚型”，生存时间更短、肿瘤易于广泛转移、患者TNM分期更高；也发现3种亚型中都存在特性高表达的膜蛋白。这些研究为精准的胃癌分子功能可视化研究提供理论依据，以开发早期胃癌的可视化分子诊断新方法。