Targeting TGF-β Receptor Signaling in Cancer
Dr. Peter ten Dijke
Section Aging and Signal Transduction
Leiden University Medical Center
The Netherlands
Biography:
Peter ten Dijke received his Ph.D. degree in 1991 from Wageningen University, The Netherlands based on his research on the identification of the third isoform of TGF-β performed at Oncogene Science, Inc., New York, USA. He did his postgraduate studies with Kohei Miyazono and Carl-Henrik Heldin at the Ludwig Institute for Cancer Research (LICR), Uppsala, Sweden. In 1994, he became group leader at LICR and in 1999 he moved to the Netherlands Cancer Institute, Amsterdam, The Netherlands. In 2005 he moved to the Leiden University Medical Center, Leiden, The Netherlands, and is currently a professor of molecular cell biology at Leiden University. His laboratory studies the molecular mechanisms by which TGF-β family members elicit their cellular effects via (co)receptors and intracellular SMAD effectors, and how subverted TGF family signaling is involved in cancer, vascular and bone diseases.
Abstract:
The transforming growth factor (TGF)-β signaling pathway is deregulated in many diseases, including cancer. In healthy cells and early-stage cancer cells, this pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. However, its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. The dual function and pleiotropic nature of TGF-β signaling make it a challenging target. Current TGF-βtargeting agents inhibit ligand or receptor function and may have unwanted side effects. This implies the need for careful therapeutic dosing of TGF-β drugs and patient selection. In my talk I will start by reviewing the rationale and challenges for the effective targeting TGF-β signaling in cancer cells and surrounding stroma. Thereafter, I will present our recent efforts to identify new druggable regulators of TGF-β receptor signaling. We employed genome wide genetic gain and loss of function screens, as well as the identification of interacting proteins of TGF-β signaling components using mass spectroscopy-based approaches. Activators of TGF-β signaling of which the expression correlated with poor prognosis were chosen for mechanistic studies. Examples that were functionally analysed are the E3 ubiquitin ligase TRAF4 and deubiquitinase USP4, which are highly expressed in breast cancer. They were found to regulate the stability of TGF-β signaling components and thereby to promote TGF-β-induced breast cancer cell invasion and metastasis. At present, we are screening for small molecules that inhibit the activity of these pro-oncogenic activators of TGF-β signaling. Our overarching aim is to develop new therapeutic drugs with selective antagonism of the tumor promoting pathways of TGF-β in cancer patients.
Time: 16:00, June. 13th, 2017 (Tuesday)
Venue: New Biology Building, Room 143
Host: Prof. Qiaoran Xi
举办单位：生命科学联合中心
