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.
| Tennis, Meredith A; Van Scoyk, Michelle; Heasley, Lynn E et al. (2010) Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1. Neoplasia 12:244-53 |
| Tennis, Meredith A; Van Scoyk, Michelle M; Freeman, Scott V et al. (2010) Sprouty-4 inhibits transformed cell growth, migration and invasion, and epithelial-mesenchymal transition, and is regulated by Wnt7A through PPARgamma in non-small cell lung cancer. Mol Cancer Res 8:833-43 |
| Heasley, Lynn E; Winn, Robert A (2008) Analysis of Wnt7a-stimulated JNK activity and cJun phosphorylation in non-small cell lung cancer cells. Methods Mol Biol 468:187-96 |
