Our lab uses a variety of experimental approaches, ranging from CRISPR/Cas9 (epi)genome editing in 2D cell culture to primary 3D organoid cultures and in vivo models to study how Wnt proteins control cell fate decisions in complex mammalian tissues.
This experimental pipeline allows us to study Wnt signaling and mammary gland biology "from man our mouse to molecule".
All projects in the lab revolve around the following three lines of research:
(i) Mechanisms of Wnt signal transduction
(ii) Translating basic principles of development to (breast) cancer research
(iii) Building new models for tissue morphogenesis and maintenance
Mechanisms of Wnt signal transduction
One of the most fascinating aspects of Wnt signaling, is the fact that the 19 different Wnt genes are expressed in highly specific and dynamic spatiotemporal patterns.
However, virtually nothing is known about the molecular mechanisms that control these dynamic yet robust patterns. Therefore, we are dissecting the (epi)genetic control mechanisms underlying tissue-specific Wnt gene expression.
For this, we use state-of-the art tools to dissect gene regulation at the chromatin level.
In addition to focusing on the tissue-specific intiation of Wnt signaling, we are also intrigued by the tissue-specific interpretation of the response in the receiving cell. Because Wnt signaling is characterized by complex and dynamic intracellular signaling events, we have extended our experimental pipeline with functional imaging studies to gain insight into the spatiotemporal dynamics of the pathway. To this end, we combine novel DNA technologies, such as CRISPR/Cas9 genome editing, with advanced microscopy (a collaboration with Mark Hink and Marten Postma).
Translating basic principles of development to (breast) cancer research
The mammary gland is a remarkably dynamic tissue. It undergoes rapid outgrowth and branching morphogenesis during puberty, side branching under the influence of cycling hormone levels, and massive proliferative expansion during pregnancy. Once lactation ceases, the mammary epithelium undergoes complete remodeling to restore the non-pregnancy state. Owing to the presence of stem cells, which have the capacity for both self-renewal and differentiation, this cycle of expansion and regression can continue to repeat itself throughout the reproductive lifespan of an organism.
The same molecular mechanisms that control normal mammary gland development and function can result in aberrant growth and cancer formation when they are disrupted. As a result, one out of every eight women will develop breast cancer during her lifetime. Moreover, tumor cells often appear to hijack self-renewal mechanisms to drive unlimited cell expansion. Therefore, it is crucial that we understand, and learn to manipulate, the biological signals that control the behavior of the different mammary cell lineages.
We hypothesize that developmental signaling pathways, such as the Wnt pathway, are targets for therapeutic intervention in breast cancer. Indeed, Wnt signaling is crucial for mammary gland development and function, but aberrant Wnt signaling can promote tumor formation. To this end, we study how changes in the level of Wnt signaling affect growth and differentiation of the mammary epithelium, using primary 3D organoid cultures of both mouse and human origin. In the long run, we hope to dissect the signaling logic of mammary gland development and function by integrating crosstalk with other developmental signaling pathways.
Building new models for tissue morphogenesis and maintenance
To visualize, track and manipulate defined cell populations in situ, more sophisticated models are needed. Therefore, we continuously aim to design and generate new drivers and reporters for wholemount imaging and in vivo lineage tracing studies.
Here, we are particularly invested in building models that allow us to visualize and quantify Wnt signaling at endogenous levels and in developing new models for improved cell segmentation and tracking.
Researchers from different disciplines are joining forces to build computational models that will one day adequately predict complex cell behavior in silico. Therefore, we also use our experimental systems to measure critical biological parameters to design and refine such models - both at the molecular level (e.g. Petrinet model for Wnt signaling, collaboration with Anton Feenstra and Jaap Heringa, VU Amsterdam, Jacobsen et al. 2016) and at the multicellular level (ongoing collaboration with Gooitzen Zwanenburg, UvA).