The effect of Wnt pathway signaling in NSCLC

描述（由申请人提供）：本提案的长期目标是定义控制肺癌细胞的致癌转化和上皮到间质转化（EMT）的信号通路。分泌的Wnt蛋白通过卷曲（Fz）家族的7个跨膜受体发出信号，调节从果蝇到人类的发育过程。通常，Wnt/Fz结合触发中间步骤，导致转录共激活因子b-连环蛋白的稳定和核积累，b-连环蛋白与TCF/LEF转录因子相互作用以激活靶基因。文献表明，Wnt通路也通过突变变得失调，并导致各种来源的人类癌症，特别是结直肠癌。然而，我们最近的工作揭示了一个新的发现，即特定的Wnt-Fzd相互作用能够通过诱导间质向上皮转化（MET）来抑制细胞生长、转化和逆转EMT （E-cadherin和MAPK是关键靶点）。虽然我们之前的工作没有在肺中检测到激活突变，但广泛的Wnt和Fz基因可以产生各种信号靶点，这些靶点可以参与肺癌细胞系的抑制和生长途径。在这项研究中，我们确定了Wnt通路在NSCLC中EMT和转化细胞生长减少中的可能作用。我们假设wnt7a - fzd9相互作用将通过b-catenin/Tcf独立机制的信号传导导致有助于减少肺癌细胞转化生长和逆转EMT的途径。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to define signaling pathways that control oncogenic transformation and epithelial to mesenchymal transition (EMT) of lung cancer cells. The secreted Wnt proteins, which signal through the Frizzled (Fz) family of seven transmembrane-spanning receptors, regulate developmental processes from Drosophila to man. Classically, Wnt/Fz binding triggers intermediate steps that result in stabilization and nuclear accumulation of the transcriptional co-activator, b-catenin, which interacts with TCF/LEF transcription factors to activate target genes. The literature demonstrates that the Wnt pathway also becomes dysregulated through mutation and contributes to human cancers of diverse origin, especially colorectal cancer. Our recent work however reveals a novel finding that specific Wnt-Fzd interactions are capable of inhibiting cell growth, transformation, and reversing EMT (E-cadherin and MAPK are critical targets) by inducing mesenchymal to epithelial transitions (MET). While no activating mutations have been detected by our previous work in lung, an extensive repertoire of Wnt and Fz genes could yield various signaling targets which could engage both inhibitory and growth pathways in lung cancer cell lines. In this study we establish a possible role for the Wnt pathway in EMT and reduced transformed cell growth in NSCLC. We hypothesize that Wnt7a-Fzd 9 interactions will lead to pathways that contribute to reduced transformed growth of lung cancer cells and reversal of EMT by signaling through b-catenin/Tcf independent mechanisms. The research environment at UCHSC and mentoring from Dr. Heasley has led to my substantial development as a clinician-scientist. In fact, I believe that I have been well prepared for my next step as an independent investigator. My research career plans as well as my proposed research project are both fully described in the body of the grant.