The effect of Wnt pathway signaling in NSCLC

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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.