Deciphering the Genetic Basis of Tumor Progression and Metastasis in Flies

描述(申请人提供)：转移是癌症患者死亡的主要原因。然而，肿瘤进展和转移的遗传基础在很大程度上是未知的。鉴于肿瘤的发生和发展过程中会发生多种基因改变，因此很难找到既发生肿瘤发生又发生转移的遗传性突变家系。恶性肿瘤细胞的基因组通常是不稳定的，这使得确定肿瘤进展的原因变化是一个令人望而生畏的挑战。此外，转移涉及多个组织，在组织培养细胞中研究这一过程尤其困难。最后，人类和哺乳动物的肿瘤进展需要很长一段时间，这增加了实验研究的复杂性。我们已经建立了一个果蝇转移模型，并进行了全基因组筛查，以确定促进肿瘤进展和转移的突变。目前已鉴定出约100个突变，它们与致癌的RAS共同促进果蝇肿瘤的进展和转移。这些苍蝇肿瘤显示了在人类恶性肿瘤中观察到的全部转移表型，包括细胞黏附丧失、基底膜降解、迁移、侵袭和继发性肿瘤形成。这种苍蝇肿瘤转移模型和已识别的突变为剖析体内转移行为和这种现象背后的机制提供了独特的机会。我们提出了以下具体目标：(1)对恢复的促进转移的突变进行基因和表型表征，以确定这些突变扰乱的基因，并记录这些突变导致的表型后果；(2)研究促进肿瘤进展和转移的癌基因合作的分子机制。我们希望这些研究将提高我们对转移行为的遗传基础的理解。鉴于许多分子和途径从苍蝇到人类都是保守的，人们进一步希望这些实验也将有助于我们了解人类肿瘤进展和转移的某些方面。

DESCRIPTION (provided by applicant): Metastasis is the major cause of mortality for cancer patients. However, the genetic basis for tumor progression and metastasis is largely unknown. Given that multiple genetic alterations occur during tumor initiation and progression, it has been difficult to find families with inherited mutations for both tumorigenesis and metastasis. The genomes of malignant tumor cells are often destabilized, which makes it a daunting challenge to pinpoint the causative alterations for tumor progression. Furthermore, metastasis involves multiple tissues and it is particularly difficult to study the process in tissue culture cells. Finally, tumor progression in humans and mammals takes a long period of time, which adds additional complication for experimental research. We have developed a Drosophila model for metastasis and have performed a genome-wide screen to identify mutations promoting tumor progression and metastasis. About 100 mutations have been identified which collaborate with oncogenic Ras in promoting tumor progression and metastasis in flies. These fly tumors exhibit a full spectrum of metastatic phenotypes observed in human malignant cancers including loss of cell adhesion, degradation of basement membrane, migration, invasion, and secondary tumor formation. This fly tumor metastasis model and the identified mutations provide a unique opportunity to dissect metastatic behavior in vivo and the mechanism underlying such phenomenon. We propose the following specific aims: (1) Genetic and phenotypic characterization for the recovered metastasis-promoting mutations to identify the genes that disrupted by these alterations and to document the phenotypic consequence caused by these mutations; and (2) Study molecular mechanism underlying oncogenic cooperation that promotes tumor progression and metastasis. We hope that these studies will improve our understanding of the genetic basis for metastatic behavior. Given that many molecules and pathways are conserved from flies to humans, it is further hoped that these experiments will also contribute to our understanding of some aspects of tumor progression and metastasis in humans.