Cancer Signaling networks and Molecular Therapeutics

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Chemical Cell Biology / Molecular Cell Biology.

Aim and focus

The aim of this research program is to understand how intra- and inter-cellular interactions control tissue homeostasis, how these processes become corrupted in cancer, and how this information can be translated into therapeutic intervention. We investigate the molecular mechanisms of various related hallmarks of cancer, including cell proliferation, genome instability, migration and invasion, angiogenesis and metastasis. Our complementary and overlapping research lines focus on the identification of novel regulators of the TGF-ß signal transduction pathway as well as the intercellular Notch-Delta pathway, identifying novel treatments for (ocular) melanoma, including p53 reactivation, identification and functional characterization of genetic alterations associated with sarcoma genesis, and the role of post-translational modifications in signal transduction, cell cycle progression, and the DNA damage response. Our research fits within the LUMC research profile Cancer Pathogenesis and Therapy (CPT).

Position in international context

We collaborate with the University of Leuven, the VIB (Leuven, Ghent; Belgium), the Peter MacCallum Cancer Centre (Melbourne, Australia), Harvard Medical School, Cambridge University, Leibniz-Research Institute for Molecular Pharmacology, the University of Dundee, The European Lead Factory and the Ludwig Institute for Cancer Research. Our current research funding includes grants from European Research Council (starting grant for Dr. A. Vertegaal) and European Union (Horizon2020: UMCure; Jochemsen).
Dr. P. ten Dijke has satellite research labs at Uppsala University, Sweden and Tsukuba University, Japan. In addition, Dr. P.  ten Dijke is a Changjian Scholar and visiting Professor at Life Science Institute, Zhejiang University, China, and has 6 PhD students/guest researchers with funding from Chinese Scholarship  Council working in his laboratory at LUMC. He organizes every other year an international meeting on TGF-ß signalling and disease.

Content / highlights / achievements

Key findings and publications in recent years include the identification of specific E3 ubiquitin ligase and deubiquitinases as potent regulators of TGF-β signaling in breast cancer progression (Zhou et al., Nature Com, 2014; Xie et al., Nature Com  2017; Zhou et al, EMBO J 2017), the pathogenic role of BMP9 in liver fibrosis (Breitkopf-Heinlein et al., Gut, 2017), the recognition of the importance of MDMX/MDM4 expression in multiple types of cancer making it a target for cancer therapy (Gembarska et al., Nat Med 2012; Haupt et al., Cell Death Dis 2015), the elucidation of novel facets of the Notch signalling pathway and pathological angiogenesis,  the identification of SUMO signalling as a target for cancer therapy (Schimmel et al., Mol Cell, 2014) and system-wide insight in SUMO signaling under regular conditions, stress conditions and in response to a DNA damaging agent (Hendriks et al. Nat Struct Mol Biol 2014 and Hendriks et al., Cell Reports, 2015). Identification of several pathognomonic genomic changes in bone and soft tissue tumors resulting in diagnostically relevant findings and targets for functional studies including EWSR1-NFATC2 translocation in novel entity in small round blue cell tumors (Szuhai et al., Clin Cancer Res. 2009) , GRM1 upregulation in chondromyxoid fibroma (Nord et al., Nat Genet, 2014), MYOD1 mutation in spindle cell rhabdomyosarcoma (Szuhai et al., J Path, 2014) and recurrent FOS translocation in epithelioid hemangioma (van IJzendoorn et al., Genes Chromosomes, Cancer 2015).

Future themes

In the future years we will focus on translating our newly identified targets and mechanisms into new cancer drugs and explore the potential of combinatorial targeting of cancer cells and surrounding stroma in animal models. We will employ exome transcriptome and genome-wide sequencing, molecular (intravital) imaging, chemical biology approaches and proteome-wide mass spectrometry analyses to address the clinical problems of therapy resistance and to treat cancer patients in a personalized manner. We will extend already established contacts with medicinal chemistry laboratories, pre-clinical groups and large pharmaceutical companies to achieve these goals.

Cohesion within LUMC

Our research is embedded within the priority area Cancer Pathogenesis and Therapy (CPT) and Leiden Network for Personalised Therapeutics. Close collaborations and integration of research activities on chemical biological approaches have been initiated with the newly formed Department of Chemical Immunology, the groups of Prof.Dr. J. Neefjes and Prof.Dr. H. Ovaa. In addition, we have close ties with groups within MCB focused on cell-based therapies and clinical departments of the LUMC such as Pathology, Oncological Orthopedic Surgery, Gastroenterology, Ophthalmology, Clinical Oncology and LACDR.