非整倍染色体在重塑细胞稳态与原癌代谢的机制研究

During mitosis, cancer cells are prone to accumulate as chromosome-missegregated aneuploid states due to the genomic unstable property. Aneuploidy is an aberrant chromosome number status, for describing cells that contain chromosomes other than multiples of the haploid number. Aneuploidy has long been recognized as a hallmark of cancer (greater than 90% solid tumors and 75% leukemia are aneuploidy), nevertheless, how aneuploidy influences cellular physiology and tumorigenesis awaits careful demonstration. With applying unique fibroblast cells that are trisomic for either chromosome 1, 13, 16 or 19, our earlier works have proved that even in the simplest single extra chromosome situation, aneuploidy can cause growth disadvantages to the cell. The stresses include imbalanced protein homeostasis, altered metabolic patterns and elevated energy requirements. In the proposal, we plan to focus on important questions including cellular homeostasis maintenance, oncogenic metabolism pathways, micro-environment and carcinogenesis. With our aneuploidy cells and mouse models, we will apply high-throughput "Chemical Biology" screen, deep sequencing for genomic and transcriptional changes, and metabolomics analysis. The collective information can help to explain how aneuploidy shapes cellular homeostasis and metabolism. Importantly, the identified key regulators and signaling pathways may have great impact to the knowledge of tumorigenesis.

癌症细胞生长分裂时容易因为染色体的不稳定性，而产生染色体分离不当的非整倍体细胞。非整倍体是一个染色体数目异常的状况，用来形容细胞内染色体的组成不是单 倍体的倍数。虽然非整倍体早已被认定为癌细胞的重要特征之一 (90%以上的肿瘤和75%以上的白血病为非整倍体)，但是对于非整倍体如何影响细胞的生理机制和细胞癌化的关系仍然有待证实。我们前期的工作利用独创的四株非整倍三体小鼠细胞观察到，仅多携带一条染色体，就能对细胞造成生长逆境，包括整体蛋白质的稳态失去平衡、代谢路径的改变和能量的需求提高等。本项目拟聚焦细胞稳态的维持、肿瘤细胞代谢路径、细胞微环境与细胞癌变等重要问题，利用特有的非整倍的细胞和小鼠模型结合高通量 "化学生物"、基因组测序、转录组测序及代谢组学等方式深入探索并阐述非整倍体如何改变细胞稳态与代谢的机制，并进一步鉴定其中的关键基因和信号通路与癌症发生的关系。

非整倍体是一种染色体数目异常的状况，为肿瘤细胞的重要特征之一。90%以上的实体瘤和50%以上的白血病都具有非整倍体的特征。本项目聚焦细胞稳态的维持、肿瘤细胞代谢路径、细胞微环境与细胞癌变等重要问题，利用特有的非整倍的细胞和小鼠模型结合高通量 “化学生物”、基因组测序、转录组测序及代谢组学等方式深入探索并阐述非整倍体如何改变细胞稳态与代谢的机制，并进一步鉴定其中的关键基因和信号通路与癌症发生的关系。在计划执行期间，我们发现非整倍体在生长过程中比正常的细胞产生更多的Ceramide。通过细胞内全体鞘脂图谱分析发现非整倍体细胞的C16-ceramide 水平为正常细胞的2倍。结合高通量化学生物的方法，筛选到特定抑制UDP-glucose ceramide glucosyltransferase (UGCG)的小分子化合物 DL-PDMP可以造成C16-ceramide 快速在非整倍体细胞累积，并启动非整倍体细胞的凋亡。在小鼠体内也发现DL-PDMP可以明显制止CIN肿瘤的生长。同时在临床数据中也显示UGCG的表达水平与结直肠癌病人的存活率息息相关，当病人的UGCG表达水平低于平均时可提升病人存活时间50-70个月。这些结果显示以UGCG作为肿瘤治疗靶点的可能性。