Research focus

​The research program of the VIB Laboratory for Molecular Cancer Biology, K.U.Leuven is devoted to the analysis of pathways governing the genesis, progression and maintenance of cancer.

Our goal is to understand how genes that have been implicated in cancer control fundamental cellular processes, such as cell death and senescence in normal cells, and how mutations that disrupt these processes impact tumor development and therapy outcome.
 
Our current research efforts follow from our recent studies on the p53 tumor suppressor. p53 is a transcription factor that functions as a central component of most cellular stress responses. The outcome of p53-mediated surveillance is closely dependent on the type of stress that activates it, ultimately steering the cell towards senescence or apoptosis. We study factors that act upstream or downstream of p53, and are able to influence or modulate p53-induced biological responses.
Our approach harnesses the power of genetics, and we devise and exploit mouse and primary cell culture models to study cancer gene function in vivo. This genetic approach allows us to explore tumorigenesis in the context of the whole organism, at times allowing us to uncover novel and unexpected links within the cancer genetic network (through in vivo screens for modifiers of p53 function), while on other occasions verifying or refuting the relevance of tissue culture data.
 
We have recently focused our attention on a number of regulators of p53 stability and activity, studying their function in normal and cancer cells:

• Mdm2, itself a target of p53, encodes a nuclear phosphoprotein that binds and inhibits transactivation by tumor protein p53, as part of an autoregulatory negative feedback loop; it encodes an E3 ubiquitin ligase that targets tumor protein p53 for proteasomal degradation as well as affecting the cell cycle, apoptosis, and tumorigenesis, possibly through its interactions with other proteins, including retinoblastoma 1 and ribosomal protein L5.
• Mdm4 (also known as Mdmx), a RING-finger-containing E3 ubiquitin ligase that regulates p53 transactivation function.
• Cop1, a RING-finger-containing E3 ubiquitin ligase that has been implicated in tumorigenesis and stress response, and previously shown to target p53 for degradation. However, our recent genetic data identify c-jun, but not p53, as a key physiological Cop1-target. Accordingly we now show that Cop1 functions as a tumor suppressor in mice.
• Nucleophosmin (NPM), a ubiquitously expressed nucleolar protein that shuttles between the nucleus and cytoplasm, which has been implicated in multiple functions including ribosomal protein assembly and transport, control of centrosome duplication, and regulation of the tumor suppressor ARF.
• Nucleostemin, a nucleolar protein that plays an essential role in maintaining the continuous proliferation of stem cells and several types of cancer cells.

An increasing amount of evidence implicates small noncoding RNAs as important components of the p53 network. We have exciting initial data that link some of the above players with the miRNA-mediated post-translational regulation pathway. Ongoing projects in the lab are pursuing these initial results using different mouse cancer models.

In the process of searching for molecular understanding of p53 regulation we are developing expertise in melanoma and retinoblastoma mouse models. While excellent to work with for technical reasons, they are intriguing because unlike in some other types of cancer, the role of p53 in melanoma and retinoblastoma is far from clear. We are developing sensitive screens to look for specific modifiers of p53 pathway in these models and to develop compounds and small molecules of therapeutic potential.

Because of the elegant genetic tools available we focus on mouse models, but having access to a large collection of human tumors we seek to find the relevance of the links between p53-modulators and effectors identified in the mouse and cancer development in the human.

Ultimately, we wish to harness for practical purposes our understanding of the molecular and cellular events that take place in response to stress and how they malfunction during tumorigenesis. Our work on Mdm4 (Mdmx) contributed to the demonstration that this protein is a specific chemotherapeutic target for treatment of retinoblastoma. Similarly, in a collaboration with others we have shown that a small-molecule MDM2 antagonist selectively activates the p53 pathway in neuroblastoma cells with wild-type p53, leading to cell cycle arrest and apoptosis.