Abstract 1095: Prox1 transcription factor and its downstream signaling - A new therapeutic target for rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) stands as the predominant soft tissue sarcoma in children, characterized by a high-grade neoplasm composed of cells resembling skeletal myoblasts. Despite being prevalent, patients with metastatic or recurrent rhabdomyosarcoma still experience poor outcomes, underscoring the necessity for novel treatments. We have recently shown that PROX1 is a critical factor in RMS tumor growth and myogenic characteristics (Gizaw NY, et al. PNAS 2022). As PROX1 has previously been associated with tumor metabolism in colorectal cancer, we investigated further its role in RMS metabolism. Our findings demonstrate that PROX1 plays a crucial role in regulating RMS cell metabolism. Specifically, silencing of PROX1 resulted in decreased lipid and oxidative metabolism, which was accompanied by an increase in glycolysis and triglyceride accumulation. RNA sequencing and Gene Set Enrichment Analysis revealed downregulation of all genes involved in the cholesterol synthesis pathway in PROX1-silenced RMS cells. Our studies further reveal that inhibiting cholesterol synthesis, akin to PROX1 silencing, can effectively inhibit RMS cell growth. Our results provide novel insights into the role of PROX1 in RMS metabolism and highlight the potential of PROX1-regulated metabolic pathways as promising targets for the development of novel RMS therapies. Citation Format: Nebeyu Y. Gizaw, Tom Böhling, Mika Sampo, Kari Alitalo, Riikka M. Kivela. Prox1 transcription factor and its downstream signaling - A new therapeutic target for rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1095.