Dissecting and Targeting Oncogenic Condensates in Pediatric Cancer
Every cell in the body must switch its genes on and off at the right time to ensure proper function. To do this, cells gather the molecular machines that read genes into tiny droplets called condensates, much the way oil forms droplets in water. These droplets act like control centers, bringing the right proteins together to turn genes on or off.
In many childhood cancers, cells contain so called “fusion proteins” that break how these condensates function. Fusion proteins occur when two genes that should stay separate get accidentally fused together, creating a new, abnormal fusion protein. These proteins invade the cell’s droplets and hijack them, forcing genes to switch on that should stay off, causing cell to grow and leading to cancer. How exactly they do this is still largely unclear. Our goal is to solve it, and then to use what we learn to design new strategies to interfere with fusion protein function.
We focus on a protein called yes-associated protein (YAP), which often forms fusion proteins in cells and that drives several childhood cancers, including brain tumors. We will use three approaches. First, using advanced microscopy techniques, we will watch single molecules in living cells to see how the normal protein and the cancer-causing fusion protein behave differently inside droplets. Second, using a powerful imaging method that can see structures just a few millionths of a millimeter across, we will map how healthy and cancerous droplets are built. By understanding their organization, we aim to understand how they function differently. And third, we aim to design strategies that selectively shut down these cancer-causing droplets to stop them from switching on the wrong genes.
This research matters for children’s health because fusion proteins cause many childhood cancers, yet almost no targeted treatments exist. Children with these tumors face high relapses and must rely on radiation and chemotherapy, which can harm a growing body for life. By revealing how fusion proteins corrupt the cell’s control centers, we aim to expose new weak points that could potentially be used to target fusion cancers more specifically.