肿瘤迁移的分子机制

Cancer is one of the most fatal diseases that threaten human health. According to a recent study, about 90% mortality of cancer patients are cause by tumor metastasis, rather than the growth of primary tumors. Thus, it would contribute significantly to the cancer treatment if regulatory genes of tumor metastasis could be identified and characterized using animal models. Drosophila melanogaster has been used as an excellent model organism to study tumorigenesis, with numerous oncogenes and tumor suppressor genes were first identified in Drosophila, and were later confirmed in mammals. Previous studies found that loss of cell polarity genes could cooperate with oncogenic Ras (RasV12) to drive tumor growth and invasion in the Drosophila eye imaginal discs. We have performed a large scale genetic screen using this model and identified 5 novel genes that regulate tumor cell migration in Drosophila. Based on the previous results, we will characterize the functions of these genes and investigate the molecular mechanism by which they modulate tumor progression, and further validate their orthologs in mammalian cells. This study is expected to provide possible drug targets and therapeutic strategies for clinical cancer treatment.

癌症是影响人类健康最为严重的疾病之一，统计数据表明, 大约90% 的恶性癌症患者死于肿瘤迁移，而非原发性的肿瘤生长。因此，利用动物模型筛选肿瘤迁移的调控基因并鉴定其作用机制对于治疗癌症有着重大意义。果蝇是生物学研究的重要模式动物，许多原癌基因和抑癌基因首先在果蝇中被发现和鉴定，然后在哺乳动物中被证实。在果蝇幼虫的眼成虫盘中下调细胞极性基因并同时过表达癌基因RasV12可诱导肿瘤发生并产生肿瘤细胞迁移表型。我们利用此表型进行了大规模的遗传筛选，寻找抑制肿瘤迁移的基因突变或RNAi，并成功发现了5个参与调控肿瘤细胞迁移的新基因。本项目拟在前期研究基础上，鉴定这些基因的功能，阐明其调控肿瘤迁移的分子机制，并在哺乳动物细胞中对其同源物进行功能验证，以期为癌症的临床治疗提供新的药物靶点和治疗方案。

癌症是危害人类健康的重要疾病之一，统计表明绝大多数癌症患者死于肿瘤迁移，而非原发性的肿瘤生长。然而，相对于肿瘤发生，我们对于肿瘤迁移的机制了解甚少。在本项目中，我们以果蝇为模式动物，建立了肿瘤发生和迁移的动物模型，并利用该模型开展了大规模的遗传筛选，发现并鉴定了多个调控肿瘤发生或迁移的新基因，阐明了其作用机制。主要结果如下：1）JNK与Hippo信号通路通过不同的机制发生相互作用，调控细胞增殖、肿瘤发生和迁移；2）原癌基因Myc通过激活puc的表达，抑制JNK介导的细胞迁移和肿瘤侵袭；3）Rho1–Wnd通路通过JNK参与调控细胞迁移和肿瘤侵袭；4）泛素链接酶Bendless通过dTRAF2，调控JNK介导的细胞迁移和肿瘤侵袭；5）JNK信号通路与Wg、Toll信号通路相互作用，调控细胞凋亡和肿瘤发生。这些结果有助于我们进一步了解肿瘤迁移的分子机制，并为癌症的临床治疗提供新的药物靶点和治疗方案。