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

描述（由申请人提供）：在遗传筛选中使用果蝇肿瘤模型，我们先前完成了基因组范围的突变筛选，这些突变与致癌Ras协同促进肿瘤生长和转移。几种鉴定的突变的表征揭示了意想不到的生物学和途径，特别强调了细胞-细胞相互作用和信号传导在介导肿瘤发展和进展中的重要性。细胞连接或顶端-基底极性的破坏导致JNK活化，这对于肿瘤细胞存活、基底膜降解、肿瘤细胞迁移以及与致癌Ras在促进肿瘤生长和转移中的克隆间合作的意外行为是必需的。事实上，肿瘤细胞的行为长期以来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（例如细胞外基质的组分）的高度影响。因此，我们研究的重点从当前资助期内确定相关基因的逻辑切换到揭示肿瘤生长和转移的肿瘤和宿主细胞相互作用的分子，细胞和发育机制。我们提出以下具体目标：（1）表征与JNK激活相关的新的RasV 12协同突变和机制。我们将描述在我们的筛选中发现的几个新的突变/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表征新的RasV 12合作突变/基因，这些基因在人类癌症中具有哺乳动物直系同源物突变，以及那些可以帮助我们理解肿瘤发展中细胞极性破坏和JNK信号传导之间的因果关系的基因;（2）剖析细胞间相互作用和促进肿瘤生长和转移的信号传导机制。我们将进一步剖析促进肿瘤发展的肿瘤和周围野生型细胞之间的信号传导，并且还将表征新的肿瘤抑制因子，其通过独特的多细胞上皮接触定义了细胞-细胞相互作用的新模式;以及（3）研究器官特异性肿瘤抑制因子。 转移我们已经发现，苍蝇肿瘤也表现出器官特异性转移行为，并将试图确定这种靶向迁移和入侵的分子基础。在 总之，在鉴定了上皮肿瘤的致病突变后，我们现在准备利用果蝇模式生物的能力来探索和揭示细胞间信号传导的分子机制，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.