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

描述（由申请人提供）：肺癌仍然是全球男性和女性癌症死亡的主要原因，非小细胞肺癌（NSCLC）占肺癌的大多数。近80%的肺癌是在晚期不可手术的阶段被诊断出来的，目前的全身治疗对肺癌患者的益处有限。此外，恶性肿瘤的发展的部分特征在于肿瘤细胞克服细胞-细胞粘附和侵入周围组织的能力。一般来说，不是原发肿瘤，而是原发肿瘤的转移是导致大多数肺癌患者死亡的原因。EMT与癌症的早期发病有关。EMT的基本特征是细胞间接触的破坏和细胞运动性的增强，这导致细胞从亲代上皮组织释放，使这些细胞更适合迁移和侵入邻近细胞（例如肿瘤侵入和扩散）。本研究的总体目标是确定非β-连环蛋白依赖性（即非经典）Wnt信号传导对NSCLC中EMT和转移的作用。迄今为止，我们的发现表明Wnt 7a的功能：1）在正常肺上皮中作为肿瘤抑制因子，和2）Wnt 7a的活化通过Fzd 9活化B-连环蛋白非依赖性（非经典）Wnt信号传导，诱导肿瘤抑制基因PPARg的活化。在以前的工作中，我们已经证明，Wnt 7a和/或Fzd 9的表达在NSCLC中经常减少，并且Wnt 7a和/或Fzd 9的缺失与上皮间质转化（EMT）、细胞极性丧失和小鼠肺癌易感性增加密切相关。基于这些发现，我们假设Wnt 7a/Fzd 9信号传导在建立细胞极性（即诱导MET）和通过调节非经典Wnt（不依赖于B-连环蛋白）信号传导减少肺中的肿瘤转移中起新的作用。此外，我们最近发现在人类肺癌中频繁的Wnt 7a启动子甲基化使Wnt 7a成为治疗NSCLC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。该项目中概述的实验策略旨在评估非经典Wnt通路对肺癌的贡献，并确定该通路的遗传靶点，可用于开发治疗肺癌的潜在小分子治疗靶点。

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.