title: Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture.
abstract: A fribotic tumor microenvironment promotes progression of cancer. In this study, we utilize a reconstituted basement membrane mimics Matrigel based three-dimensional organotypic culture (rBM 3-D) to investigate the mechanisms that mediate the tumor promoting effects of the fibrogenic mediators TGF-β1 and type I collagen (Col-1) on lung adenocarcinoma cells. Similar to normal alveolar epithelial cells, the well-differentiated lung adenocarcinoma cells in rBM 3-D culture undergo acinar morphogeneis that features polarized epithelial cell spheres with a single central lumen. Either TGF-β1 or Col-1 modestly distorts acinar morphogenesis. On the other hand, TGF-β1 and Col-1 synergistically induce a transition from acinar morphology into stellate morphology that is characteristic of invasive and metastatic cancer cells. Inhibition of the Src kinase activity abrogates induction of stellate morphology, activation of Akt and mTOR, and the expression of tumor promoting genes by TGF-β1 and Col-1. To a similar extent, pharmacological inhibition of mTOR abrogates the cellular responses to TGF-β1 and Col-1. In summary, we demonstrate that TGF-β1 and Col-1 promote stellate morphogenesis of lung cancer cells. Our findings further suggest that the Src-Akt-mTOR axis mediates stellate morphogenesis. These findings also indicate that rBM 3-D culture can serve as an ideal platform for swift and cost-effective screening of therapeutic candidates at the interface of the tumor and its microenvironment.
authors: Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. bshan@tulane.edu.
authors: Hong T
authors: HT
authors: Nguyen
authors: Yan
authors: Y
authors: Zhuang
authors: Lichun
authors: L
authors: Sun
authors: Steven P
authors: SP
authors: Kantrow
authors: Jay K
authors: JK
authors: Kolls
authors: Zongbing
authors: Z
authors: You
authors: Ying
authors: Y
authors: Zhuo
authors: Bin
authors: B
authors: Shan