EMT controlled phenotype switching drives malignant progression

Speaker: Geert Berx
Department: Molecular and Genetic Oncology Lab, Ghent University, Belgium
Location: Erasmuc MC Rotterdam
Date: May 24, 2017
Author: Teun Huijben

Geert Berx is introduced by one of our teachers Riccardo Fodde as one of the pioneers in the field of the epithelial-mesenchymal transition (EMT). After this introduction he starts to give us an introduction on EMT.

As the name implies, EMT is the transition of an epithelial cell to a mesenchymal cell. The epithelial cells are polar and very tightly connected to there surrounding cells, thereby forming a clear boundary between the underlying tissue and the outside world. To become a mesenchymal cell, the mesenchyme is the connective tissue lying underneath the epithelium, the cell has to loose its polarity and connections to other cells. This is done by losing the cell-cell interaction protein E-Cadherin (epithelial Cadherin). E-Cadherin is down-regulated as a result of binding of transcription factors to specific E-boxes near the promotor.

The most important transcription factor doing this, and discovered by Geert Berx himself, is ZEB2. If ZEB2 is high in expression the E-cadherin is down-regulated, resulting in less cell-cell interactions enabling EMT. Control experiments in different mouse models and human cell lines showed that knocking-out ZEB2 resulted in more E-cadherin and no EMT, proving this theory.

The reason why EMT is widely studied is because of its importance in cancer. When malignant epithelial cells undergo EMT, they can travel through the mesenchyme to the blood and travel then to new places to form metastases. For a long time, people thought of EMT in a very binary way; a cell is either epithelial or mesenchymal. However, Geert and his colleagues proved that there are also multiple transitional states between epithelial and mesenchymal cells, and they showed at least 8 different metastable intermediates. The distinct states differ in levels of amongst other things E-cadherin, EpCAM and ZEB2. In both normal tissue as tumors, a wide variety of these states is found, indicating that the EMT system is way more difficult than thought.

Further research into the importance of ZEB2 in EMT and tumor formation resulted in many new insights. ZEB2 appeared also important in the maintenance of stem cells, spontaneous tumor formation and the p53 pathway. However, in the study of ZEB2 importance in human melanoma cell lines they found something interesting. When ZEB2 was knocked-out the tissue didn’t differentiate anymore, and high levels of its counterpart ZEB1 were measured. Indicating that ZEB2 is important in differentiation and proliferation. Further studies showed that ZEB1 is important in stem cell maintenance and tumor invasion. This resulted in a clear model where either ZEB1 of ZEB2 is present, supported by experimental data.

However, when ZEB2 was over-expressed, they found more metastases, which contradicted the current model. Further investigation resulted in the finding that TNF (tumor necrose factor) down-regulates the ZEB2 protein, resulting in higher ZEB1 levels and thereby creating more metastases. All of this knowledge together resulted in an oscillating model of ZEB1 and ZEB2 levels during tumor progression (see Figure 1).

Schermafbeelding 2017-05-24 om 13.43.33Figure 1. The levels of ZEB1 and ZEB2 oscillate during the progression of cancer. In the primary tumor ZEB2 is highly expressed, resulting in a high proliferation. During the transient state, ZEB2 is down-regulated paving the way for ZEB1 to be active and facilitate invasion. In the metastases again ZEB2 is present to stimulate proliferation and tumor outgrowth.  

After all, I found the talk by Geert Berx very interesting. Although it made very clear how many players are important in the progression of cancer and how difficult it is to do research on it.

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