Laboratory of Cancer Signals
Section leader
Peter ten Dijke
P.ten_Dijke(AT)lumc.nl
Laboratory of Cancer Signals
In order to properly respond to growth-stimulatory and growth-inhibitory signals, cells posses multiple signal transduction pathways, consisting of specific molecules that transmit these signals from their receptors to the nucleus, where transcription factors convert them into specific gene expression programs. To be able to integrate information from different types and doses of stimuli that can reach a cell simultaneously or within short (repeated) intervals, signaling molecules from distinct pathways interact on many levels, both on the membrane, in the cytoplasm and in the nucleus, thereby forming large cellular networks which are often localized to specific sub-cellular structures. During carcinogenesis and cancer progression cells loose their ability to correctly respond to growth inhibitory signals, and/or show increased sensitivity to growth-stimulatory and pro-invasive signals. This is the result of genetic defects, such as mutation, deletion or amplification of specific signaling molecules, or due to epigenetic events such as gene silencing.
We are interested in the detection, identification and functional characterization of signaling complexes and intermediates that distinguish cancer cells from normal cells, or that differ during the different stages of tumor progression. These complexes might function as diagnostic and/or prognostic markers and become targets for therapeutic intervention. In our current work, we focus on components of the TGF-ß-Smad and MAP kinase-AP-1 pathways, two pathways that play critical roles in tumor progression and interact on multiple levels. TGF-ß-Smad signaling components in fact play dual roles in cancer, as they inhibit cell cycle progression and cell survival during early carcinogenesis, but often enhance tumor cell migration, invasion and metastasis during the later stages. MAP kinases (ERK, JNK and p38) and their transcription factor AP-1 targets can also regulate cancer cell mobility and invasion. Moreover, MAP kinases and AP-1 transcription factors can either inhibit or stimulate cell proliferation and survival, dependent on cell type, cell stimuli, the oncogenic changes and the cellular environment.
The work is done in close cooperation with the Signal Transduction Section of the Department of Molecular Cell Biology at the Leiden University Medical Center in the Netherlands, the Department of Genetics and Pathology of the Rudbeck Laboratory of Uppsala University, and the TGF-ß signaling group and the Laboratory of Molecular Pathology at LICR.
| Selected Publications | |
| Publications 2009-2010 (see also annual reports) | |
| Sundqvist A, ten Dijke P, van Dam H. (2011) Signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial plasticity. Breast Cancer Res, in press. | |
| Naber HPN, Wiercinska E, Pardali E, van Laar Nirmala E, Sundqvist A, van Dam H, van der Horst G, van der Pluijm G, Heckmann B, Danen EH, ten Dijke P.(2011) BMP-7 inhibits TGF-ß-induced invasion of breast cancer cells through inhibition of integrin?ß3 expression. Cellular Oncology, Sep 21. | |
| Hawinkels LJ and ten Dijke P. (2011) Exploring anti-TGF-ß therapies in cancer and fibrosis. Growth Factors, Aug; 29(4):140-52. | |
| Drabsch Y and ten Dijke P (2011) TGF-ß signaling in breast cancer cell invasion and bone metastasis. Journal of Mammary Gland Biology and Neoplasia, Jun; 16(2):97-108. | |
| Meulmeester E and ten Dijke. P. (2011) The dynamic role of TGF-ß in cancer. J. Pathology, 223:205-18. | |
| van der Heide L, van Dinther M, Moustakas A, ten Dijke P. (2011) TGFß activates mitogen- and stress-activated protein kinase1 to attenuate cell death. J. Biol. Chem, Feb 18; 286(7):5003-11. | |
| Meulmeester E and ten Dijke P (2010). Integration of transcriptional signals at the tumor cell invasive front. Cell Cycle, 9, 13. | |
| Wiercinska E, Naber HP, Pardali E, van der Pluijm, G, van Dam H, ten Dijke P. (2010) The TGF-ß/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat, Sept 5. | |
| Baan B, Pardali E, ten Dijke P and van Dam H (2010) In situ proximity ligation detection of cJun/AP-1 dimers reveals increased levels of cJun/Fra1 complexes in aggressive breast cancer cell lines in vitro and in vivo. Mol Cell Proteomics, 9:1982-90. | |
| Group Members: | ||
| Position | Name | |
| Group leader: | Prof. Dr. Peter ten Dijke | |
| Post-doctoral fellow | Dr. Anders Sundqvist | |
| Senior researcher | Dr. Hans van Dam | |