Abstract TGFβ is considered as a strong inducer of epithelial-mesenchymal transition (EMT) of tumor cells, promoting metastasis. Whereas acute TGFβ exposure induces growth arrest, chronic TGFβ exposure provokes invasive properties with resistance to TGFβ-induced growth arrest. However, the effect of chronic TGFβ exposure on acquired invasive characteristics of tumor cells is not fully determined. We established a trans-differentiated (TD) A549 cell model by chronic exposure of TGFβ1, with clear EMT phenotypes including high invasiveness. Of interest, elevated invasiveness of TD cells after additional TGFβ1 treatment was achieved even in the significantly downregulated Smad2/3 dependent signaling compared to control cells. We demonstrated that Snail and Slug, the expression of which was highly correlated with poor prognosis of lung cancer patients, were clearly increased in TD cells upon TGFβ1 stimulation due to high protein stability. The increased stability of Snail and Slug in TD cells was attributed to elevated inhibitory phosphorylation of GSK3β, which was caused by higher Akt activity. We demonstrated that dramatically increased integrin β3 by prolong TGFβ1 exposure was responsible for high activity of Akt and subsequent high protein stability of Snail and Slug. Thereby, our data suggest that targeting of integrin β3-mediated signaling would be a potential therapeutic strategy to inhibit invasive properties of TGFβ-stimulated lung cancer. Citation Format: Gab-Yong Bae, Hyuk-Jin Cha. Sustained exposure to TGFβ1 increases the stability of Snail and Slug via integrin β3-Akt-GSK3β signaling, facilitating tumor cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B54.