Comprehensive cell contact tracing (C3T)

In multicellular organisms from worms to humans, cell-cell communication is essential for proper development and homeostasis. Cells are equipped with a plethora of receptors, which relay physical interactions at the cell surface into the cell nucleus, resulting in a molecular and subsequently often phenotypic change of the cell. Interactions with cells in their surroundings also critically influence the behavior of diseased cells (including cancer), and these cell s in turn are known to influence their environment. Although of utmost importance, it has remained difficult to investigate cell-cell interactions and specifically resulting cellular changes at scale and in a natural setting. To overcome this hurdle, we will leverage recent developments in the fields of synthetic biology, microfluidic devices, in vivo imaging, and computational biology, and use these technologies for comprehensive cell contact tracing (C 3T). Working with zebrafish as an experimentally amenable model system, C3T will use cells that have been genetically engineered such that selected cell contacts elicit a response that enables a molecular recording of these interactions. A query cell will carry an activator for this receptor. Thus, contacts with this query cell (and only with this cell) will be engraved in interacting cells. This makes it possible to explore cell contacts throughout the entire zebrafish organism under the microscope or using high-throughput molecular assays. In our pilot project, we will use C3T to follow the history of cell interactions of tumor cells through the body on their way to forming metastases. As metastasis remains the leading cause of cancer- related deaths, but the process is intrinsically difficult to study outside the endpoints (i.e., the primary tumor and the metastasis), this proof-of-principle application may open up an entirely new way of channeling research into transient phases of this process (mobilization, extravasation, etc.). If successful, our approach will also be transferrable to other model organisms and research questions.

No additional funding sources recorded.