Novel Synthetic Biology Approach to Monitor Transient Tumour-Immune Cell Interaction in vivo

该项目旨在通过结合合成生物学和活体成像方法来监测肿瘤转移模型中肿瘤细胞和巨噬细胞之间的动态相互作用。转移，即肿瘤细胞向次级器官的扩散，占癌症死亡的90%以上，是癌症研究最紧迫的挑战。越来越多的临床和临床前证据表明，肿瘤/免疫细胞的相互作用对癌症的进展和转移具有深远的影响(Kitamura等人，2015年)。先前的研究表明，肿瘤细胞与巨噬细胞的相互作用对转移特别关键(钱等人，2011年)。这种相互作用是动态和复杂的，因为不同的巨噬细胞亚群具有不同的促肿瘤或抗肿瘤功能，受组织微环境的不同调节。活体成像为显示相关活体组织环境中细胞间的动态相互作用提供了一种强有力的方法。然而，记录这些瞬时的相互作用并解释它们对疾病进展的影响一直是具有挑战性的。合成生物学允许通过传感器和致动器合成系统将新功能工程到细胞中。最近，已经开发出合成嵌合受体并在细胞中进行了改造，以对与邻近细胞上的特定配体接触做出反应(Morsut等人，2016)。在这个项目中，将开发新的合成受体细胞系来检测肿瘤细胞与不同亚群的巨噬细胞的相互作用，这些巨噬细胞带有不同的细胞表面标记。这些细胞将通过荧光蛋白表达报告接触，并允许实时监测巨噬细胞/肿瘤细胞在体外和小鼠癌症模型中的相互作用，从而揭示这些细胞间接触在癌症进展中所起的关键作用。该项目将为疾病机制提供新的见解，并突出有效治疗这种致命疾病的潜在治疗策略。

This project aims at monitoring the dynamic interactions between tumour cells and macrophages in cancer metastasis models, by combining synthetic biology and intra-vital imaging approaches.Metastasis, the spreading of tumour cells to secondary organs, accounts for over 90% of death from cancer and is the most pressing challenge for cancer research. Mounting clinical and preclinical evidences indicate that tumour/immune cells interactions have profound effects on cancer progression to metastasis (Kitamura et al., 2015). Previous studies have illustrated that tumour cells interaction with macrophages, a type of innate immune cells, is particularly critical for metastasis (Qian et al., 2011). The interaction is dynamic and complex, as there are different macrophage subsets with pro- or anti- tumour function differentially regulated by tissue microenvironment. Intra-vital imaging provides a powerful method to illustrate dynamic cell-cell interaction in relevant in vivo tissue environment. However, recording these transient interactions and interpreting their effect on disease progression has been challenging.Synthetic biology allows the engineering of new functions into cells through sensor and actuator synthetic systems. Recently, synthetic chimeric receptors have been developed and engineered in cells, to respond to contact with specific ligands presented on neighbouring cells (Morsut et al., 2016). In this project, new synthetic receptor cell lines will be developed to detect tumour cell interactions with different subsets of macrophages that bear distinct cell surface markers. These cells will report contact through fluorescent protein expression and allow real-time monitoring of macrophage/tumour cells interaction both in vitro and in mice cancer models, shedding light on the pivotal role played by these intercellular contacts in cancer progression. This project will provide novel insights into the disease mechanism and highlight potential therapeutic strategies to effectively treat this lethal disease.