紫杉类药物通过诱导肿瘤细胞分裂期阻滞诱发凋亡或衰老，进而阻止细胞的增殖。虽然成功应用多年，但原发和继发耐药局限了这类药的疗效，而目前对耐药机理了解的还很少。我们前期的研究发现紫杉醇处理的细胞在分裂阻滞期特异合成Notch2受体，并通过下游通路促进细胞在下一间期的存活和耐药。在Notch信号介导耐药的研究中，我们发现了很有趣的现象：与细胞内的实验比较，小鼠体内干扰Notch2更加显著地抑制耐药的产生。据此我们推测肿瘤微环境介导的细胞间通讯在Notch2参与的耐药调控中发挥重要作用，初步研究证实细胞应激上调的Notch2参与了微环境的重塑，这些改变很可能反馈调节肿瘤细胞的命运。本项目拟进一步揭示Notch2调控微环境的方式和功能，阐明微环境中不同细胞和因子反馈调控Notch2信号的机制，从而对微环境决定阻滞后细胞命运的机理有更深入的认识，为理解紫杉类药物作用和耐药机理，及新的组合治疗提供思路。

Taxanes inhibit the proliferation of tumor cells by inducing mitotic arrest that activates intrinsic apoptosis or senescence. Although taxanes were successfully used in clinical for many years, primary and acquired resistance limits the efficacy of these drugs. So far the mechanism of drug resistance is not clear yet. Our previous studies found that the Notch2 receptor was specifically synthesized during prolonged mitosis in paclitaxel-treated cells, which promote cell survival in the next interphase after prolonged mitosis through multiple downstream pathways. Furthermore, when we study the drug resistance function of the Notch2 receptor in vivo, an exciting phenomenon that interfering with the Notch2 signaling pathway has a more significant inhibitory effect on taxanes resistance in vivo than in vitro was found. Based upon these clues, we speculated that the intercellular communication, which was mediated by the tumor microenvironment, played a vital role in regulating the Notch2 signaling pathway in taxanes resistance. In our previous work, we confirmed that Notch2 signaling is up-regulated during taxol induced cellular stress, which is further involved in the reshaping of the tumor microenvironment. At the same time, these changes in the tumor microenvironment are further likely to regulate tumor cell fates as a feedback loop. This project will intend to reveal the ways and mechanisms by which Notch2 helps to reshape the tumor microenvironment. Furthermore, it would clarify the mechanism by which different cells and factors in tumor microenvironment would involve in regulating the Notch2 signaling pathway in tumor cells in return. This study would provide a deeper understanding of the mechanisms of tumor microenvironment, which later determines cell fates after prolonged mitosis. Through this project, we will have a better understanding of how taxanes exert their anti-tumor functions and the taxanes resistance mechanism that could provide us better perspectives for combination therapies, which could be enhanced by antimitotic agents.