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

果蝇肿瘤生长和转移中细胞间相互作用的机制

• 批准号: 8297214
• 负责人: TIAN XU
• 金额: $ 30.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-05 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297214
• 关键词: Address; Animal Model; Apical; Apoptosis; Architecture; Basement membrane; Behavior; Biology; Cancer Biology; Cell Adhesion; Cell Communication; Cell Polarity; Cell Proliferation; Cell Survival; Cells; Characteristics; Defect; Development; Drosophila genus; Environment; Epithelial; Exhibits; Extracellular Matrix; Funding; Gene Mutation; Genes; Genetic Screening; Growth; Human; Individual; Intercellular Junctions; Link; MAPK8 gene; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutate; Mutation; Neoplasm Metastasis; Oncogenic; Organ; Orthologous Gene; Pathway interactions; Play; Process; Regulation; Research; Role; Signal Pathway; Signal Transduction; Time; Tumor Suppressor Proteins; base; cell type; extracellular; fly; genome wide association study; in vivo; migration; neoplastic cell; novel; tool; tumor; tumor growth; tumorigenic

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. PUBLIC HEALTH RELEVANCE: Cell-cell interaction is critical for maintaining proper epithelial architecture and integrity involved in the regulation of cellular proliferation, adhesion, cell shae, and apoptosis, all of which are aberrant in malignant tumors. Having identified causative mutations for epithelial tumors that share common defects in cell polarity and signaling pathways, we now have the opportunity to use fly tumor model to explore and unravel the molecular mechanisms underlying intercellular signaling that is central to understanding human tumor malignancy.

描述（由申请人提供）：我们之前使用果蝇肿瘤模型进行遗传筛选，完成了全基因组筛选与致癌Ras协同促进肿瘤生长和转移的突变。几个已识别突变的表征揭示了意想不到的生物学和途径，特别强调了细胞间相互作用和信号传导在介导肿瘤发生和进展中的重要性。细胞连接或顶端-基底极性的破坏导致 JNK 激活，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 的克隆间合作促进肿瘤生长和转移的意外行为至关重要。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（例如细胞外基质的成分）的高度影响。因此，我们的研究重点从逻辑上从识别当前资助期间涉及的基因转向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）表征新的 RasV12 协同突变和与 JNK 激活相关的机制。我们将表征在我们的筛选中发现的几个新突变/基因，目的是识别和研究新型肿瘤抑制因子并了解 JNK 是如何被激活的。我们的努力将集中在表征人类癌症中哺乳动物直系同源突变的新型 RasV12 协同突变/基因，以及那些可以帮助我们了解肿瘤发展中细胞极性破坏与 JNK 信号传导之间因果关系的基因； （2）解析促进肿瘤生长和转移的细胞间相互作用和信号传导机制。我们将进一步剖析肿瘤与周围野生型细胞之间促进肿瘤发展的信号传导，还将表征一种新型肿瘤抑制因子，它通过独特的多细胞上皮接触定义了细胞间相互作用的新模式； (3) 研究器官特异性 转移。我们发现果蝇肿瘤也表现出器官特异性转移行为，并将尝试确定这种靶向迁移和侵袭的分子基础。在 总之，在确定了上皮肿瘤的致病突变后，我们现在准备利用果蝇模型生物的力量来探索和揭示细胞间信号传导的分子机制，这对于理解癌症生物学至关重要。 公共健康相关性：细胞间相互作用对于维持适当的上皮结构和完整性至关重要，这些结构和完整性涉及细胞增殖、粘附、细胞形状和凋亡的调节，所有这些在恶性肿瘤中都是异常的。在确定了在细胞极性和信号通路方面具有共同缺陷的上皮肿瘤的致病突变后，我们现在有机会使用果蝇肿瘤模型来探索和揭示细胞间信号传导的分子机制，这对于理解人类肿瘤恶性肿瘤至关重要。