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Published online 14 January 2002. doi:10.1083/jcb.200109037
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© The Rockefeller University Press, 0021-9525/2002/1/299 $5.00
The Journal of Cell Biology, Volume 156, Number 2, January 21, 2002 299-314

Article

Ras and TGFß cooperatively regulate epithelial cell plasticity and metastasis

: dissection of Ras signaling pathways



Elzbieta Janda1, Kerstin Lehmann2, Iris Killisch1, Martin Jechlinger1, Michaela Herzig1, Julian Downward2, Hartmut Beug1 and Stefan Grünert1

1 Institute of Molecular Pathology, A-1030 Vienna, Austria
2 Signal Transduction Laboratories, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

Address correspondence to Stefan Grünert, Dr. Bohrgasse 7, A-1030, Vienna, Austria. Tel.: 43-1-79730. Fax: 43-1-798-7153. E-mail: grunert{at}nt.imp.univie.ac.at

Multistep carcinogenesis involves more than six discrete events also important in normal development and cell behavior. Of these, local invasion and metastasis cause most cancer deaths but are the least well understood molecularly. We employed a combined in vitro/in vivo carcinogenesis model, that is, polarized Ha-Ras–transformed mammary epithelial cells (EpRas), to dissect the role of Ras downstream signaling pathways in epithelial cell plasticity, tumorigenesis, and metastasis. Ha-Ras cooperates with transforming growth factor ß (TGFß) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers. EMT requires continuous TGFß receptor (TGFß-R) and oncogenic Ras signaling and is stabilized by autocrine TGFß production. In contrast, fibroblast growth factors, hepatocyte growth factor/scatter factor, or TGFß alone induce scattering, a spindle-like cell phenotype fully reversible after factor withdrawal, which does not involve sustained marker changes. Using specific inhibitors and effector-specific Ras mutants, we show that a hyperactive Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas activation of phosphatidylinositol 3-kinase (PI3K) causes scattering and protects from TGFß-induced apoptosis. Hyperactivation of the PI3K pathway or the Raf/MAPK pathway are sufficient for tumorigenesis, whereas EMT in vivo and metastasis required a hyperactive Raf/MAPK pathway. Thus, EMT seems to be a close in vitro correlate of metastasis, both requiring synergism between TGFß-R and Raf/MAPK signaling.

Key Words: PI3K; MAPK; TGFß; EMT; metastasis


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