Receptor Cross-Talk in Early Metastatic Dissemination

描述（由申请人提供）：上皮性卵巢癌（EOC）将影响今天在美国出生的每69名妇女中的1名。目前，80%新诊断为EOC的女性已经患有转移性疾病，这表明对转移过程的干预将改善EOC女性的长期生存。转移通过一种独特的机制发生，涉及非粘附细胞作为多细胞聚集体（MCA）脱落到腹膜腔中，随后腹膜内（IP）植入，并且通常与腹膜腹水相关。目前尚不清楚调节从自由浮动MCA到危及生命的腹膜锚定转移性病变的终末转变的因素。上一个资助期的研究强调了可溶性微环境调节剂EGF和溶血磷脂酸（LPA）在调节上皮（E）-钙粘蛋白（Ecad）表达和功能中的作用。这些机制的研究产生了令人兴奋的新数据，金属蛋白酶催化的Ecad胞外域脱落，可溶性Ecad胞外域在人EOC腹水中的作用，以及由连接完整性改变引起的2-连环蛋白动力学的变化。此外，我们进行了一个详细的免疫组化分析Ecad表达在原代人EOC，开发了一个面板的测定，以评估MCA的动力学和转移的成功，并确定了一组基因产物通过改变细胞的机械环境调节。这些结果形成了目前的假设，即钙粘蛋白转换和IP机械生物学积极有助于转移成功的基础。目标1中的研究将集中于钙粘蛋白转换和MCA动力学，使用一组钙粘蛋白修饰的细胞系和一套体外测定，旨在机械地评估钙粘蛋白组合物对EOC转移中关键细胞事件的影响。目标2中的实验将评价腹膜机械生物学改变对MCA转移成功的一系列测量的影响，并将确定IP机械力是否影响间皮对转移性植入的接受性。目的3将联合收割机分析人类肿瘤和小鼠IP转移模型，以直接检查体内改变的钙粘蛋白谱和转移性播散。这些研究的长期目标是培养对EOC转移的分子水平理解，这对于开发有效靶向转移性疾病的EOC特异性治疗是必要的。 公共卫生相关性：叙述上皮性卵巢癌（EOC）将影响今天在美国出生的每69名妇女中的1名。目前，80%新诊断为EOC的女性已经患有转移性疾病。这些研究的长期目标是获得EOC转移的分子水平的理解，以设计更有效地靶向转移性疾病的策略。

DESCRIPTION (provided by applicant): Epithelial ovarian carcinoma (EOC) will affect 1 out of every 69 women born in the US today. Currently, 80% of women newly diagnosed with EOC already have metastatic disease, indicating that intervention in the metastatic process will improve long-term survival of women with EOC. Metastasis occurs through a unique mechanism involving shedding of non-adherent cells as multi-cellular aggregates (MCAs) into the peritoneal cavity followed by intra-peritoneal (IP) implantation, and is often associated with peritoneal ascites. The factors that regulate the terminal transition from free-floating MCA to life-threatening peritoneally anchored metastatic lesion are currently unknown. Studies in the previous funding period highlighted the role of the soluble microenvironmental regulators EGF and lysophosphatidic acid (LPA) in regulation of epithelial (E)-cadherin (Ecad) expression and function. These mechanistic studies generated exciting new data on metalloproteinase-catalyzed Ecad ectodomain shedding, the role of the soluble Ecad ectodomain in human EOC ascites, and on changes in 2-catenin dynamics resulting from altered junctional integrity. Further, we performed a detailed IHC analysis of Ecad expression in primary human EOC, developed a panel of assays with which to evaluate MCA dynamics and metastatic success, and identified a set of gene products regulated by altering the mechanical environment of the cell. These results form the basis of the current hypothesis that cadherin switching and IP mechanobiology actively contribute to metastatic success. Studies in Aim 1 will focus on cadherin switching and MCA dynamics using a panel of cadherin-modified cell lines and a suite of in vitro assays designed to mechanistically evaluate the effect of cadherin composition on key cellular events in EOC metastasis. Experiments in Aim 2 will evaluate the effect of altered peritoneal mechanobiology on the suite of measures of MCA metastatic success and will determine whether IP mechanical forces affect mesothelial receptivity to metastatic implantation. Aim 3 will combine analysis of human tumors and murine IP metastasis models for a direct examination of altered cadherin profiles and metastatic dissemination in vivo. The long-term goal of these studies is to cultivate a molecular level understanding of EOC metastasis, necessary for the development of EOC-specific therapies that effectively target metastatic disease. PUBLIC HEALTH RELEVANCE: Narrative Epithelial ovarian cancer (EOC) will affect 1 out of every 69 women born in the US today. Currently 80% of women newly diagnosed with EOC already have metastatic disease. The long-term goal of these studies is to gain a molecular level understanding of EOC metastasis to design strategies to more effectively target metastatic disease.