Mechanisms of Cell-Cell Interaction in Tumor Growth and Metastasis in Flies

描述(申请人提供)：在基因筛查中使用果蝇肿瘤模型，我们之前完成了全基因组筛查，寻找与致癌RAS协同促进肿瘤生长和转移的突变。对几个已识别的突变的表征揭示了意想不到的生物学和途径，并特别强调了细胞-细胞相互作用和信号在调节肿瘤发展和进展中的重要性。JNK是肿瘤细胞存活期、基底膜降解、肿瘤细胞迁移以及与原癌基因RAS协同作用促进肿瘤生长和转移所必需的。事实上，肿瘤细胞的行为长期以来一直被认为受到其微环境、与周围野生型细胞的相互作用以及细胞外环境(如细胞外基质的成分)的高度影响。因此，我们的研究重点在逻辑上从识别当前资助期的相关基因转向揭示肿瘤与宿主细胞相互作用导致肿瘤生长和转移的分子、细胞和发育机制。我们提出了以下具体目标：(1)鉴定新的RasV12协同突变和与JNK激活相关的机制。我们将在我们的屏幕上描述几个新的突变/基因，目的是识别和研究新的肿瘤抑制因子，并了解JNK是如何被激活的。我们的工作将集中在以下几个方面：(1)鉴定在人类癌症中与哺乳动物同源基因发生突变的新型RasV12协同突变/基因，以及那些有助于我们理解细胞极性中断与肿瘤发生中JNK信号之间的因果联系的基因；(2)剖析促进肿瘤生长和转移的细胞间相互作用和信号机制。我们将进一步剖析肿瘤和周围野生型细胞之间促进肿瘤发展的信号，并将表征一种新的肿瘤抑制因子，它通过独特的多细胞上皮接触定义一种新的细胞-细胞相互作用模式；以及(3)研究器官特异性 转移。我们发现苍蝇肿瘤也表现出器官特异性的转移行为，并将试图确定这种靶向迁移和侵袭的分子基础。在……里面 综上所述，在确定了上皮性肿瘤的致病突变后，我们现在准备利用果蝇模式生物的力量来探索和揭开细胞间信号转导的分子机制，这是理解癌症生物学的核心。

DESCRIPTION (provided by applicant): Using a Drosophila tumor model in a genetic screen, we previously completed a genome-wide screen for mutations that cooperate with oncogenic Ras in promoting tumor growth and metastasis. Characterization of several identified mutations revealed unexpected biology and pathways, and especially highlighted the importance of cell-cell interaction and signaling in mediating tumor development and progression. Disruption of cell junction or apical-basal polarity leads to JNK activation, which is essential for tumor cell survivl, basement membrane degradation, tumor cell migration, and the unexpected behavior of interclonal cooperation with oncogenic Ras in promoting tumor growth and metastasis. Indeed, the behavior of tumor cells has long been recognized to be highly influenced by its microenvironment, interaction with surrounding wild type cells, and the extracellular milieu such as components of the extracellular matrix. The focus of our research, thus, logically switches from identifying the involved genes in the current funding period to uncover the molecular, cellular, and developmental mechanisms underlying tumor and host cell interactions for tumor growth and metastasis. We propose the following specific aims: (1) Characterizing novel RasV12 cooperating mutations and mechanisms related to JNK activation. We will characterize several new mutations/genes identified in our screen with the aim to identify and study novel tumor suppressors and to understand how JNK is activated. Our efforts will be focused on characterizing novel RasV12 cooperating mutations/genes that have mammalian orthologs mutated in human cancers and those genes that could help us to understand the causal link between disruption of cell polarity and JNK signaling in tumor development; (2) Dissecting cell-cell interaction and signaling mechanisms in promoting tumor growth and metastasis. We will further dissect the signaling between tumor and surrounding wild type cells that promotes tumor development, and will also characterize a novel tumor suppressor, which defines a new mode of cell-cell interaction via unique multicellular epithelial contacts; and (3) Studying organ-specific metastasis. We have discovered that the fly tumors also exhibit organ-specific metastasis behavior, and will try to identify the molecular basis for this targeted migration and invasion. In summary, having identified causative mutations for epithelial tumors, we are now poised to utilize the power of the Drosophila model organism to explore and unravel the molecular mechanisms underlying intercellular signaling that is central to the understanding of cancer biology.