van Amerongen Lab - Developmental, Stem Cell & Cancer Biology

- Swammerdam Institute for Life Sciences - University of Amsterdam -  


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 in early development and mammary gland biology at multiple scales or, put differently, "from man our mouse to molecule".

All projects in the lab revolve around the following three themes:

(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 regulation at the chromatin level, using state-of-the art tools.
This line of research was established using the NWO VIDI grant that was awarded to Renée in 2014.

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 (past and ongoing collaborations with Mark Hink and Marten Postma at the UvA).
This line of research was initially set up using the MacGillavry start-up funds awarded to Renée in 2013 and has received follow up funding from NWO (2019).

Ultimately, different cell types activate different gene expression patterns once the Wnt signal has been propagated to the nucleus, resulting in tissue-specific interpretation of the response. To understand how these tissue-specific CTNNB1/TCF target gene programs are controlled, we integrate experimental and bioinformatics approaches to dissect the governing principles and tissue-specific aspects.
This line of research was started using the KWF career development award that Renée received in 2013.

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.
This line of research was started using the KWF career development award that Renée received in 2013. It received follow up funding from KWF (2017).

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.
This work has received funding from KWF (2015).

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 develop and refine such models - both at the molecular, cellular and multicellular level. This integrative, systems-based approach is critically dependent on collaborators with complementary expertise (past on ongoing collaborations with Anton Feenstra and Jaap Heringa at the VU; Gooitzen Zwanenburg at the UvA; and Marten Postma at the UvA).

We are excited to expand this research theme to early embryonic development using an in vitro gastruloid model system, thanks to an NWO-XL consortium grant (awarded to Renée and Thijs in 2022, collaboration with Hendrik Marks at RU Nijmegen, Jop Kind at the Hubrecht Institute and Tineke Lenstra at the NKI). This will also allow us to study the crosstalk between and integration of Wnt and Bmp/Nodal signaling.