Lipid-Sensing ETV6 Vulnerability in Ewing Sarcoma
| Ewing sarcoma is a rare and aggressive cancer that primarily affects children and adolescents, often arising in bone or soft tissue. Patients with metastatic or relapsed disease have poor outcomes, and current treatment relies on chemotherapy and radiation regimens that have remained largely unchanged for decades. A key challenge is that Ewing sarcoma is driven by a fusion protein, EWS/FLI1, rather than mutations that can be targeted with existing drugs. Our lab recently discovered that another protein, ETV6, is critical for maintaining the cancerous state in Ewing sarcoma and is largely dispensable in normal tissues. ETV6 acts as a transcriptional repressor and works in cooperation with EWS/FLI1 to silence genes that promote differentiation. Blocking ETV6 causes EWS/FLI1 to bind different sites in the genome and switch from supporting tumor growth to suppressing it. Although ETV6 is a promising target, it lacks the typical features such as enzymatic activity or defined binding pockets that most drugs depend on. To overcome this, we conducted a screen to identify pathways that regulate ETV6 activity. We found that Ewing sarcoma cells are selectively vulnerable to increased lipid signaling, particularly through a molecule called phosphatidic acid (PA). PA directly binds to ETV6, interferes with its ability to form complexes, and removes it from the genome, resulting in loss of repression and reduced tumor cell survival. This vulnerability appears to be specific to Ewing sarcoma and is mechanistically distinct from general cytotoxic effects. We hypothesize that Ewing sarcoma relies on a tightly controlled lipid environment to maintain ETV6 function and that increasing PA levels could disrupt this dependency and impair tumor growth. Our project has three main objectives. Aim 1 will determine why Ewing sarcoma cells are selectively sensitive to PA elevation by comparing lipid and gene expression responses across cancer types. Aim 2 will map how PA interacts with ETV6 and how this affects its ability to bind chromatin and regulate gene expression. Aim 3 will explore two therapeutic strategies: blocking the PA-binding site on ETV6 and using small molecules to raise PA levels in cells. We will test these approaches in cell-based models and 3D tumor cultures. This research introduces a new way to target transcription factors that have long been considered undruggable by exploiting their sensitivity to lipid signaling. If successful, it will lay the groundwork for a new class of therapies for Ewing sarcoma and potentially other pediatric cancers that depend on similar metabolic constraints |