Regulation of Wnt Signaling in Invasive Colon Cancer

 描述(申请人提供)：结肠癌是美国男性和女性癌症死亡的第三大原因。它的定义是结肠上皮从受控的隐窝生长转变为不受控制的增殖和侵袭周围的粘膜。驱动这一转化的主要突变是以典型的Wnt信号通路为靶标，通过稳定ç-catenin来迫使Wnt靶基因的过度表达和Wnt的活性。尽管有这种慢性的Wnt激活，但肿瘤内的信号活性水平是不同的，有高和低Wnt活性的区域，这表明环境信号与该途径存在串扰。由于每五名结肠癌患者中就有一人首次被确诊为转移性疾病，而且这些患者在确诊后的典型生存时间为五年， 迫切需要了解Wnt活性的波动以及肿瘤微环境如何影响结肠癌的进展和侵袭。本项目主要研究结肠癌中Wnt信号的异质性是如何通过基质细胞的自分泌信号和串扰信号的调节来建立的。我们的实验室和其他人最近发现，通过抑制Wnt配体的分泌来减少结肠癌细胞中的自分泌Wnt信号会导致细胞迁移和侵袭的增加。根据已发表的研究和我的初步发现，我的主要假设是结肠癌中Wnt信号活性在癌症侵袭和转移过程中下调。我将从三个具体目标来阐述这一假设。第一个特定的目标是确定参与抑制运动的Wnt信号通路。加州大学欧文分校开发的划痕分析、三维肿瘤球体分析和新型微流控设备将用于测量不同Wnt途径受到干扰时癌细胞表型的变化。在第二个目标中，我将确定参与该途径激活的结肠癌细胞表达的受体。最后，我将具体定义配体：受体相互作用(S)TAT参与抑制细胞迁移。确定这一机制对于了解结肠癌如何转移到远处器官具有潜在的治疗益处。

 DESCRIPTION (provided by applicant): Colon cancer is the third leading cause of cancer deaths in men and women in the United States. It is defined by the transformation of the colon epithelium from regulated crypt growth to uncontrolled proliferation and invasion into the surrounding mucosa. The primary mutations that drive this transformation target the canonical Wnt signaling pathway by stabilizing ß-catenin to force overexpression of Wnt target genes and Wnt activity. Despite this chronic Wnt activation, the level of signaling activity within the tumoris heterogeneous, with regions of high and low Wnt activity, suggesting environmental signals crosstalk with the pathway. As one in five colon cancer patients are first identified with metastatic disease, and the typical survival for these patients post-diagnosis is five years, there is a pressing need to understand fluctuations in Wnt activity and how the tumor microenvironment can influence colon cancer progression and invasion. This project focuses on how heterogeneity of Wnt signaling in colon cancer is established through its modulation both by autocrine signaling and crosstalk signaling from stromal cells. Our lab and others have recently discovered that decreasing autocrine Wnt signaling in colon cancer cells through inhibition of Wnt ligand secretion leads to increased cell migration and invasion. Based upon published research and my preliminary findings, my overarching hypothesis is that Wnt signaling activity in colon cancer is down regulated during cancer invasion and metastasis. I will address this hypothesis in three specific aims. The first specific aim will identify the Wnt signaling pathway involved in inhibiting mobility. Scratch assays, three-dimensional tumor spheroid assays, and novel microfluidic devices developed here at UC Irvine will be used to measure changes in cancer cell phenotype when various Wnt pathways are perturbed. In the second aim, I will identify the receptors expressed by colon cancer cells that participate in the activation of the pathway. Lastly, I will specifically define the ligand: receptor interaction(s) tat are involved in inhibiting cell migration. Identifying this mechanism has potential therapeutic benefits in understanding how colon cancer metastasizes to distant organs.