Abstract LB-275: Epithelial-mesenchymal transition rewires mechanisms upstream of PI3K-dependent growth.

Tumors that show evidence of epithelial to mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. EMT may alter the molecular requirements for growth and survival in different contexts, but the underlying mechanisms remain incomplete. Given the heterogeneity along the EMT spectrum between and within tumors it is important to define the requirements for growth and survival in cells with an epithelial or mesenchymal phenotype to maximize therapeutic efficacy. We have established an inducible cell line model in which a tamoxifen regulatable Twist-ER fusion protein is stably expressed in the H358 non-small cell lung cancer cell line. Upon tamoxifen addition, cells undergo EMT and provide a system in which we can compare the growth and survival requirements directly related to EMT, removing confounding factors present when comparing different cell lines. Using this system we have found that while cells require PI3K for growth before and after the transition, the mechanisms through which they can activate the signal are altered. Specifically, before EMT basal PI3K is maintained by autocrine activation of ErbB3 signaling, despite the presence of an activating Ras mutation. Loss of ErbB3 ablates proliferation in pre-EMT cells suggesting that oncogenic KRas is not sufficient to drive growth in this context. After induction of EMT ErbB3 expression is downregulated along with downstream PI3K signal, leading to a loss of cell autonomous proliferation. Restoration of PI3K signaling by either re-expression of ErbB3, activated p110, or through stimulation with various growth factors is able to restore growth in post-EMT cells. These data have implications for therapeutic targeting of different RTKs, suggesting that within a heterogeneous tumor environment, only a subset of cells may respond to such treatments. Furthering the understanding of how EMT alters signaling through specific pathways will facilitate the design of more efficacious treatment strategies to target all cells along this phenotypic spectrum. Citation Format: Megan B. Salt, Frank McCormick. Epithelial-mesenchymal transition rewires mechanisms upstream of PI3K-dependent growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-275. doi:10.1158/1538-7445.AM2013-LB-275