There exist a number of well-defined markers of the epithelial to mesenchymal transition (EMT), a process crucial for the outgrowth of tumours to new areas of the body (metastasis), and now a signalling protein Pyk2 has been welcomed into the fold.
Focal Adhesion Kinase (FAK) is an established regulator of EMT in response to the pro-EMT signalling protein Tumour Growth Factor Beta (TGFβ), a recent study has revealed that some of FAK’s functions also require Pyk2 and suggests important roles for Pyk2 in tumour metastasis. A previous study by Sun et al. from The University of Hong Kong has also described a role for Pyk2 in driving EMT in liver cancer (hepatocellular carcinoma).
Normal human breast cells transformed to be cancer-like and cells from patients with aggressive (invasive ductal cell carcinoma, with reaccurance after 5 years) show high levels of Pyk2 protein. One breast cancer cell line is a mixture of less aggressive and more aggressive cancer cells, within these different cell populations the group observed vastly different levels of Pyk2 protein.
This increased Pyk2 expression was associated with increased growth of cells in a three dimensional tumour-like environment. In fact, growth of cells in this 3D model can enhance Pyk2 expression in breast cancer cell lines in a manner that is independent of the pro-EMT factor TGFβ. When growing two dimensionally (i.e. on a plastic culture surface) breast cancer cells show low levels of Pyk2, however treatment TGFβ could increase Pyk2 levels, but not to the same extent as observed in the 3D model. The group suggest that the 3D model exhibits autocrine TGFβ signalling (where TGFβ released by one cell acts directly upon the same cell). Importantly, not only do the cells make more Pyk2, but there are higher levels of the active form of Pyk2 (phosphorylated Pyk2). The signalling mechanism which links TGFβ to the increased Py2k levels observed was shown to involve the actions of a transcription factor called Smad4, this pathway was observed clearest in aggressive breast cancer cells.
Metastasis requires a dramatic change in the shape of cells (a novel mechanism of this was previously described in a past post); the classical EMT shape change is induced by TGFβ, however this was independent of Pyk2. It appears that FAK is the key protein involved here.
The group went on to show that whilst up-regulation of Pyk2 in breast cancer cells is required along with FAK for acquisition of an EMT signature, Pyk2 alone is indispensable for their ability to outgrow their initial “primary” tumour site and metastasise to the lung. Pyk2 could therefore present a therapeutic target for the treatment of invasive, pre-metastatic breast cancer.
Wendt MK, Schiemann BJ, Parvani JG, Lee YH, Kang Y, Schiemann WP.
TGF-β stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer.
Oncogene. 2012 Jun 18. doi: 10.1038/onc.2012.230. [Epub ahead of print]
Sun CK, Ng KT, Lim ZX, Cheng Q, Lo CM, Poon RT, Man K, Wong N, Fan ST.
Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition.
PLoS One. 2011 Apr 20;6(4):e18878. doi: 10.1371/journal.pone.0018878.