Regulation of Wnt Signaling in Invasive Colon Cancer

 描述（由申请人提供）：结肠癌是美国男性和女性癌症死亡的第三大原因。其定义为结肠上皮从受调节的隐窝生长转变为不受控制的增殖并侵入周围粘膜。驱动这种转化的主要突变通过稳定β-连环蛋白以迫使Wnt靶基因和Wnt活性过表达来靶向经典Wnt信号传导途径。尽管存在这种慢性Wnt激活，但肿瘤内的信号传导活性水平是异质的，具有高和低Wnt活性的区域，这表明环境信号与该途径发生串扰。由于五分之一的结肠癌患者首先被确定为转移性疾病，并且这些患者诊断后的典型生存期为五年， 目前迫切需要了解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。该项目的重点是如何在结肠癌中的Wnt信号的异质性是通过自分泌信号和基质细胞的串扰信号的调节建立的。我们的实验室和其他人最近发现，通过抑制Wnt配体分泌减少结肠癌细胞中自分泌Wnt信号，导致细胞迁移和侵袭增加。基于已发表的研究和我的初步发现，我的总体假设是，结肠癌中的Wnt信号传导活性在癌症侵袭和转移过程中下调。我将在三个具体目标中阐述这一假设。第一个具体目标将确定参与抑制流动性的Wnt信号通路。划痕试验，三维肿瘤球体试验，以及在UC Irvine开发的新型微流体装置将用于测量各种Wnt途径受到干扰时癌细胞表型的变化。在第二个目标中，我将确定参与激活该途径的结肠癌细胞表达的受体。最后，我将具体定义参与抑制细胞迁移的配体：受体相互作用。识别这种机制对于理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.