284169 Role of ERK Activity in Epithelial-to-Mesenchymal Transition in Lung Cancer

Thursday, November 1, 2012: 3:33 PM
Somerset East (Westin )
Janine Buonato and Matthew J. Lazzara, Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA

Epithelial-to-mesenchymal transition (EMT) is a cellular program critical for tumor invasion and metastasis.  During EMT, cells with initially epithelial characteristics (e.g., expression of markers such as E-cadherin and a high degree of cell spreading) become less proliferative and increasingly migratory as they take on mesenchymal characteristics (e.g., expression of markers such as vimentin and reduced cell-cell contacts).  Compared to their epithelial counterparts, cells with mesenchymal characteristics also tend to be more resistant to a variety of targeted therapeutics used in the treatment of cancer (e.g., inhibitors of specific kinases).  Thus, developing a quantitative understanding of the factors which control EMT may provide a new framework for improving tumor response to targeted therapeutics.  In this presentation, we will discuss our recent work demonstrating that the activity of the extracellular regulated kinase (ERK) pathway is of critical importance in the determination of mesenchymal characteristics in non-small cell lung carcinoma (NSCLC).  Working with a panel of human NSCLC cell lines, we have demonstrated that ERK activity is required for EMT initiated by exogenous transforming growth factor beta (TGF-beta), one of the most well-established mediators of EMT.  Moreover, we have demonstrated and quantitatively determined the extent to which ERK activity levels govern an epithelial versus mesenchymal state even in the absence of TGF-beta.  More specifically, we have demonstrated that three distinct cellular perturbations affecting ERK activity levels, each of which may be observed in NSCLC, can alter the balance of epithelial and mesenchymal characteristics of NSCLC cells.  These perturbations include the mutational status of the cellular kinase KRAS, amplification of ERK itself, and altered rates of endocytosis of the epidermal growth factor receptor.  Finally, we have also connected this control of epithelial/mesenchymal marker expression by ERK to associated changes in cellular phenotypes including cellular migration speed in scratch closure assays, proliferation, and cell death response to targeted chemotherapeutics.  Importantly, our results demonstrate that the observed cell phenotypic changes occur with a time scale which corresponds to that with which epithelial and mesenchymal marker expression changes in response to ERK activity perturbation.  This time scale is much larger than that for changes in ERK activity itself, reflecting the need for downstream ERK-dependent processes to effect phenotypic changes.  Overall, our results suggest a number of opportunities to rationally control EMT processes in cancer to engineer improved clinical outcomes for patients with NSCLC.

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