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。由于在肿瘤发生和发展过程中会发生多种遗传改变，因此很难找到同时具有肿瘤发生和转移遗传突变的家族。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致病改变成为一项艰巨的挑战。此外，转移涉及多个组织，在组织培养细胞中研究转移过程尤其困难。最后，人类和哺乳动物的肿瘤进展需要很长一段时间，这给实验研究增加了额外的复杂性。我们已经开发了一个果蝇转移模型，并进行了全基因组筛选，以确定促进肿瘤进展和转移的突变。在果蝇中，大约有100个突变已被确定与致癌Ras协同促进肿瘤的进展和转移。这些蝇类肿瘤表现出在人类恶性肿瘤中观察到的全谱转移表型，包括细胞粘附丧失、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鉴定的突变提供了一个独特的机会来解剖体内的转移行为和这种现象的机制。我们提出以下具体目标：(1)对恢复的促进转移突变进行遗传和表型表征，以确定被这些改变破坏的基因，并记录这些突变引起的表型后果；(2)研究促癌合作促进肿瘤进展和转移的分子机制。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。鉴于从果蝇到人类的许多分子和途径是保守的，我们进一步希望这些实验也将有助于我们对人类肿瘤进展和转移的某些方面的理解。

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.