Wnt 7a and Its Role in EMT and Lung Cancer Metastasis

描述(申请人提供)：肺癌仍然是世界上男性和女性癌症死亡的首要原因，非小细胞肺癌(NSCLC)占肺癌的大部分。近80%的肺癌是在晚期无法手术时被诊断出来的，目前的全身治疗对肺癌患者的益处不大。此外，恶性肿瘤的发展在一定程度上表现为肿瘤细胞克服细胞间黏附和侵袭周围组织的能力。一般来说，大多数肺癌患者死亡的原因不是原发肿瘤，而是原发肿瘤的转移。EMT与癌症的早期发病有关。EMT的基本特征是破坏细胞间的接触，增强细胞的运动性，导致细胞从亲本上皮组织中释放出来，使这些细胞更适合向邻近细胞的迁移和侵袭(如肿瘤的侵袭和扩散)。本研究的总体目标是确定b-连环蛋白非依赖性(即非典型的)Wnt信号在非小细胞肺癌EMT和转移中的作用。到目前为止，我们的研究结果表明，Wnt7a在正常肺上皮细胞中发挥作用：1)在正常肺上皮细胞中作为肿瘤抑制因子；2)Wnt7a的激活通过Fzd9激活b-连环蛋白非典型的Wnt信号，诱导肿瘤抑制基因PPARg的激活。在以前的工作中，我们已经证明Wnt7a和/或Fzd9在NSCLC中的表达经常降低，并且Wnt7a和/或Fzd9的缺失与小鼠上皮向间充质转化(EMT)、细胞极性丧失以及肺癌易感性的增加密切相关。基于这些发现，我们推测Wnt7a/Fzd9信号在建立细胞极性(即诱导MET)和通过调节非典型的WnT(b-连环蛋白非依赖性)信号来减少肺肿瘤转移方面发挥了新的作用。此外，我们最近发现Wnt7a在人类肺癌中频繁启动子甲基化，这使得Wnt7a成为治疗非小细胞肺癌的潜在有吸引力的未来治疗靶点。 公共卫生相关性：肺癌是美国男性和女性癌症死亡的主要原因。事实上，今年死于肺癌的人数将超过乳腺癌、前列腺癌和结直肠癌的总和。本项目中概述的实验策略旨在评估非典型性Wnt途径对肺癌的贡献，并确定该途径的遗传靶点，以开发潜在的小分子治疗肺癌靶点。

DESCRIPTION (provided by applicant): Lung cancer remains the leading cause of cancer death in the world for both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. Nearly 80% of lung cancer is diagnosed at an advanced inoperable stage, and current systemic therapy offers only modest benefits for lung cancer patients. In addition, the development of malignant tumors is in part characterized by the ability of a tumor cell to overcome cell-cell adhesion and to invade surrounding tissue. In general, it is not the primary tumor, but metastasis from the primary tumor that is responsible for the demise of most lung cancer patients. EMT has been associated with the early onset of cancer. The essential feature of EMT are disruption of intercellular contacts and the enhancement of cell motility, which leads to the release of cells from parental epithelial tissue making these cells more suitable for migration and invasion to neighboring cells (e.g. tumor invasion and dissemination). The overall goal of this study is to determine the role of b-catenin independent (i.e. non- canonical) Wnt signaling on EMT and metastasis in NSCLC. Our findings to date suggest that Wnt 7a functions: 1) as a tumor suppressor in normal lung epithelia, and 2) that activation of Wnt 7a activates b- catenin independent (non-canonical) Wnt signaling through Fzd9, inducing activation of the tumor suppressor gene PPARg. In previous work, we have demonstrated that Wnt 7a and/or Fzd 9 expression is frequently reduced in NSCLC, and that the loss of Wnt 7a and/or Fzd 9 is strongly associated with epithelial to mesenchymal transition (EMT), loss of cellular polarity, and increased susceptibility to lung carcinogenesis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd9 signaling plays a novel role in establishing cell polarity (i.e. inducing MET), and reducing tumor metastasis in the lung by regulating non-canonical Wnt (b- catenin independent) signaling. Moreover, our recent finding of frequent promoter methylation of Wnt 7a in human lung cancer makes Wnt 7a a potentially attractive future therapeutic target in the treatment of NSCLC. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death for both men and women in the United States. In fact, more deaths will occur this year due to lung cancer than breast, prostate, and colorectal cancers combined. The experimental strategies outlined in this project are designed to evaluate the contribution of the non-canonical Wnt pathway to lung cancer and to identify genetic targets of this pathway that could be used to develop potential small molecular therapeutic targets for the treatment of lung cancer.