靶向非整倍体与鞘脂稳态的肿瘤干预研究

Aneuploidy is a hallmark of cancer cells, about 90% of solid tumors and more than 50% of leukemia cells are characterized with aneuploidy status. Aneuploidy plays multiple roles in tumorigenesis. Aneuploidy can elicit gene mutations, epigenetic changes, and even though large-scale chromosomal recombination during mitosis (chromotripsis). Those are collectively beneficial for tumors to adapt or progress in a new microenvironment. On the other hand, aneuploid per se triggers unbalanced protein homeostasis, increased cellular energy requirement and metabolic changes similar to Warburg effect, thus adds stresses to cell growth. We have established an in vitro screening platform to explore small molecules that selectively inhibit the proliferation of aneuploid cells. This allows us to reveal further aneuploidy impacts in cell growth, and also with an applicative value in cancer therapy. Previously we have found a glucosylceramide synthase (GCS) antagonist can effectively inhibit the proliferation of chromosome instability (CIN) colorectal cancer cells. In this proposal, we plan to proceed the observation to the level of whether aneuploidy causes sphingolipid dysregulation. We aim to illuminate the key factors or bioactive molecules to explain the mechanism. The identified regulators and signaling pathways may have great impact on clinical diagnosis and treatment for cancer therapy.

非整倍体是癌细胞的重要标志之一, 大约有90%的实体瘤和50%以上的白血病细胞具有非整倍体现象。非整倍体在肿瘤发生发展中扮演多重角色，如可以增加细胞中的基因突变、表观遗传改变，甚至进一步造成大规模的染色体破碎，使肿瘤容易在不同微环境中适应或获得生长优势。但另一方面，非整倍体也会造成不利于肿瘤生长的情形，如细胞的蛋白质稳态失衡、细胞能量需求升高和代谢路径改变等。我们建立了一套三体细胞筛选平台，检测能特异性抑制非整倍体细胞的小分子。这些细胞株不仅可以揭示更多非整倍体影响细胞生长的机制，而且有助于发现抑制肿瘤生长和复发的药物。在前期工作中，我们发现葡糖神经酰胺合成酶GCS抑制剂可以有效抑制非整倍体的结直肠癌细胞生长。本项目将进一步探讨染色体的不稳定性是否为鞘脂代谢异常的关键，并寻找造成鞘脂代谢异常的关键分子与机制。通过非整倍体靶向鞘脂代谢异常，本项目将可能为临床肿瘤诊断和治疗提供新思路。

非整倍体是癌症的一个主要特征之一，90%的肿瘤和50%以上的血癌细胞都有非整倍体的现象。非整倍体会给机体带来基因组损伤，降低细胞生长速度。同时也会引破坏细胞内蛋白和能量稳态。通过细胞内全体鞘脂图谱分析, 我们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，我们筛选UDP-glucose ceramide glucosyltransferase (GCS)的拮抗小分子化合物 DL-PDMP。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。在小鼠模型中发现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GCS的表达水平与结直肠癌病人的存活率相关，当病人的GCS低表达时可以增加病人存活时间4-6年以上。这些结果显示以GCS作为肿瘤治疗靶点的可能性。除此之外，我们发现DL-PDMP与临床化疗药物紫杉醇(Taxol)有很好的加成性，能够更有效的抑制癌症细胞的生长。靶向Ceramide不仅可以做为治疗癌症的新方法，并且能够与化疗药物Taxol协同作用，增强Taxol的治疗效果，降低其使用剂量。