Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis

By E. Janda, K. Lehmann, I. Killisch, M. Jechlinger, M. Herzig, Julian Downward, H. Beug, S. Grünert. Journal of Cell Biology, 2002

632 citations recorded by the source corpus.

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 β (TGFβ) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers. EMT requires continuous TGFβ receptor (TGFβ-R) and oncogenic Ras signaling and is stabilized by autocrine TGFβ production. In contrast, fibroblast growth factors, hepatocyte growth factor/scatter factor, or TGFβ 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 TGFβ-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 TGFβ-R and Raf/MAPK signaling.

Subfields: Hepatology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/6b64e8800d0fb929b793c7fac56d22bd3901bcfe

How researchers see this paper

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In Hepatology

1. R. Weinberg

In Molecular Biology

1. R. Weinberg
2. R. Derynck
3. A. Moustakas
4. C. Heldin
5. K. Miyazono
6. H. Ikushima
7. Xin-Hua Feng
8. Jing Yang

In Oncology

1. R. Weinberg
2. R. Derynck
3. Jing Yang
4. K. Miyazono
5. H. Ikushima
6. J. Brugge
7. Angeliki Voulgari
8. A. Pintzas

Citations in the corpus

• Smad-dependent and Smad-independent pathways in TGF-β family signalling (2003, background): “Furthermore, the cooperation between Ras/MAPK and TGF-β signalling in tumour cell behaviour does not seem to be compatible with the defective Smad signalling in Ras-transformed cell”
• TGF-β and epithelial-to-mesenchymal transitions (2005, background): “Vimentin expression has been suggested as a critical marker to distinguish ‘true, complete EMT’ from ‘cell scattering’ or ‘partial EMT’ (Janda et al., 2002a; Grunert et al., 2003).”
• A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition (2009, background): “Transforming growth factor-β (TGF-β) cooperates with signalling pathways, such as Ras and Wnt, to induce EM”
• Transforming Grown Factor-β Signaling in Immunity and Cancer (2019, neutral): “TGF-β is a potent inducer of EMTs but this function critically depends on inputs from the RAS-MAPK pathway (David et al., 2016; Horiguchi et al., 2009; Janda et al., 2002).”
• Integration of TGF‐β/Smad and Jagged1/Notch signalling in epithelial‐to‐mesenchymal transition (2004, background): “Importantly, the metastatic potential of certain carci- nomas is associated with cooperative signalling by activated Ras and autocrine TGF-b inducing an irreversible EMT phenotype (Janda et al, 2002).”
• Modelling glandular epithelial cancers in three-dimensional cultures (2005, background): “Subsequent studies have shown that a hyperactive RAF–ERK pathway is required for EMT and invasive behaviou”
• NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2 (2007, background): “Several signaling pathways have been implicated in EMT of Eph4 cells including ras activation and TGF-b1-activated signals (Janda et al., 2002; Bhowmick et al., 2004).”
• TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. (2005, background): “The data also suggest that TGF-β is sufficient to elicit a transient but fully developed EMT response in normal epithelial cells without the need for predisposing oncogenic transformation as documented for the Ras oncogene (Janda et al., 2002; Oft et al., 2002; Grünert et al., 2003).”
• Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. (2008, background): “…cell lines and in mouse tumor models, activation of the TGF-b pathway at the later stages of tumor progression has been shown to promote EMT in carcinoma cells, which allows these cells to invade the ECM in culture and to spread to distant organs in mice (Janda et al., 2002; Oft et al., 1998).”