In close collaboration with the group of Peter ten Dijke we focus on components of the transforming growth factor (TGF)ß-Smad and MAP kinase-AP-1 pathways, which play critical roles in tumor progression and the cellular response to anti-cancer drugs and radiation, including therapy-resistance. These pathways interact at multiple levels.TGFb-Smad signaling components play dual roles in cancer, as they can 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 AP-1 transcription factor 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. We have used amongst others in situ proximity ligation assays (PLA) to study the involvement of the various AP-1 and Smad complexes in TGFb-Smad induced cell invasion. In addition, we have used transcriptome and ChIP sequencing approaches to identify critical TGFb-regulated complexes and target genes that regulate tumor-cell properties such as epithelial-mesenchymal transition, invasion and drug-responses. The research is performed both in the Department of Cell and Chemical Biology at the LUMC and the Department of Medical Biochemistry and Microbiology at Uppsala University.


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