Inducing Neuroblastoma Differentiation In Vivo
Neuroblastoma is the most common cancer in the first year of life, metastasizes in over 60% of patients, and once metastasis has occurred, 5-year survival rates decrease to less than 50%. Current therapy often relies on a large number of chemotherapeutic agents, and survival remains poor in comparison to other childhood malignancies. Here, we propose to apply our developmental neuroscience expertise to identify and manipulate cell signaling pathways in vivo in specific microenvironmental contexts, with the goal of promoting neuroblastoma differentiation into harmless neurons that quickly die. By focusing on both microenvironmental sources of signaling and their cell autonomous effects in malignant cells in vivo, we aim to uncover new druggable targets that impact neuroblastoma cells’ ability to differentiate. If successful, our approach will reveal a regulatory circuit consisting of several proteins, laying the groundwork for multi-target drug development of combinatorial therapies.
Project Goal:
To pursue neuroblastoma differentiation, we have developed and validated a customized model system in which human neuroblastoma cells are injected into streams of neural crest stem cells in live zebrafish embryos. Cells are then tracked at high spatiotemporal resolution, and their behavior is quantitatively analyzed. This unique experimental canvas has revealed that particular microenvironments halt neuroblastoma progression by differentiating malignant cells into neurons that quickly undergo apoptosis, and we have identified several molecular components as essential for this process. Now, our goal is to discover unexpected contributors to neuroblastoma differentiation, with a focus on proteins that have been previously shown to play entirely different roles in neuroblastoma survival but which our data suggest can regulate differentiation as well. In combination with our previous findings, we will build a growing network of signaling pathways that informs the therapeutic targeting of multiple proteins, with the goal of more effectively pushing neuroblastoma cells to differentiate and die. Thus, our findings could eventually facilitate the development of multi-drug treatment regimens that improve patient outcomes and survivorship.
