Characterisation of cooperation between cell polarity regulators and oncogenes in tumourigenesis using Drosophila

癌症在一生中的某个阶段影响1-3人，因此对医学科学具有重要意义。癌症是通过改变正常细胞增殖控制、分化、细胞死亡或细胞运动的突变积累而产生的。此外，最近的研究表明，肿瘤环境（细胞之间的相互作用）可能是癌症发展的一个主要因素。然而，这很难在哺乳动物模型中进行研究。在这个提议中，我们使用遗传上可适应的模型系统，醋蝇果蝇，来研究肿瘤的发展，使用定义的突变。为了探索果蝇肿瘤发生的机制，我们正在使用一个系统，我们可以在正常组织的背景下制造突变组织的补丁（克隆），一个更忠实地模仿哺乳动物癌症发展的系统。我们已经观察到，细胞形状所需的某些基因（细胞极性基因，如scrib）在限制致癌基因（肿瘤引起基因，如Ras的激活等位基因）在果蝇肿瘤发展中的作用方面是重要的。因此，细胞极性基因的突变与致癌突变合作，导致侵袭性肿瘤的产生。在基因筛选中，我们已经确定了以类似方式与scrib或活化Ras突变体合作的进一步基因。在本提案中，我们试图表征这些基因在肿瘤发生和探索其作用机制。该项目的预期结果是阐明在整个生物体的背景下肿瘤发生的新基因和机制。由于细胞增殖和信号蛋白的保护，这一建议与了解人类癌症有关。

Cancers affect 1-3 people at some stage during their lifetime and therefore is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. In addition, recent studies have shown that the tumour environment (the interaction between cells) can be a major factor in the development of the cancer. However, this is difficult to study in mammalian models. In this proposal we use the genetically amenable, model system, the vinegar fly Drosophila, to investigate the development of tumours using defined mutations. To explore mechanisms of tumourigenesis in Drosophila, we are using a system where we can make patches (clones) of mutant tissue within the context of normal tissue, a system that more faithfully mimics the development of mammalian cancer. We have observed that certain genes required for cell shape, (cell polarity genes, such as scrib) are important in limiting the action of oncogenes (tumour- causing genes, such as activated alleles of Ras) in the development of tumours in Drosophila. Thus, mutants in cell polarity genes cooperate with oncogenic mutations to result in the generation of invasive tumours. In a genetic screen, we have identified further genes that act in a similar manner to cooperate with mutants in scrib or activated Ras. In this proposal we seek to characterise these genes in tumourigenesis and to explore their mechanism of action. The expected outcome of this project is to elucidate novel genes and mechanisms of tumourigenesis in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.