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Winn Lab

 

Contacts: 

Phone:     (303) 724-6092

Email:       robert.winn@ucdenver.edu


Research Activity:

Project 1: The Role of the Non-canonical Wnt pathway in NSCLC.

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. The overall goal of this study is to determine the role of b-catenin independent (i.e. non-canonical) Wnt signaling on the initiation and promotion of NSCLC. Our findings to date suggest two seemingly unrelated Wnt 7a functions: 1) that Wnt 7a acts 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 (see fig. below). 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 carcinogensis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd9 signaling plays a novel role in establishing and/or maintaining cell polarity, and functions as a tumor suppressor in the lung epithelium 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.

Aim 1:

Determine if the loss of Wnt 7a alters aspects of cell growth that are consistent with the transformed phenotype as measured by anchorage independent growth, cell growth, migration/ invasion and cell polarity in 3D cell culture.  

Aim 2:

The reconstitution of Wnt 7a/Fzd 9 in NSCLC results in reduced transformed cell growth. The closely related Fzd 9 and 10 receptors are a subfamily of Fzd receptors. We will ask if the activation of downstream Wnt targets are specific to Wnt7a/Fzd 9 vs. Wnt 7a/Fzd 10 signaling in the lung. 

Aim 3:

Determine the mechanisms of Wnt 7a/Fzd9 tumor suppression in vivo.

Proposed Model

       

  

Project 2: Wnt 7a and its role in EMT and Lung cancer metastasis.

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 Fzd 9, inducing activation of the tumor suppressor gene Peroxisome Proliferator-Activated Receptor-gamma (PPARgsee fig. below). In previous work, we have also 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 carcinogensis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd 9 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.

Aim 1:

Determine if the loss of Wnt 7a alters metastasis and EMT as measured by migration/ invasion and cell polarity in 3D cell culture.  

Aim 2:

Determine the mechanisms of Wnt 7a/Fzd 9 suppression of metastasis in vivo. 

Project 3: Prostacyclin Inhibits Non Small Cell Lung Cancer Growth by a Frizzled 9 Dependent Pathway that is blocked by Secreted Frizzled Related Protein 1.

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human Non-Small Cell Lung Cancer (NSCLC) and to define the mechanism of iloprost’s tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with expression of the cell-surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of PPARg. Silencing of Fzd 9 blocked PPARg activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost’s activation of PPARg and inhibition of transformed growth. Interestingly, sFRP1 a well-known inhibitor of Wnt/Fzd signaling also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of non-canonical Wnt signaling maybe important for the inhibition of transformed cell growth.  We have several other projects (e.g. micro-RNA association with Wnt pathway signaling; LRP5 and NSCLC, etc.) that are under development and experiments are currently underway. 

Big Goals: To develop more sophisticated animal models to determine if and when EMT occurs in an in vivo modeling system. Also to develop better in vivo lung cancer models.