Thursday, November 21, 2024
11/21/2024
Project Summary/Abstract Rhabdomyosarcoma (RMS) is a common aggressive pediatric soft tissue sarcoma. Despite many rigorous clinical trials, the survival rate for high-risk patients has not increased in three decades. Furthermore, pediatric RMS patients receive an aggressive combination of surgery, chemotherapy, and radiation, leading to life-long treatment related consequences, underscoring the need to understand the basic biology of RMS to identify new molecular targets. RMS is commonly viewed through the lens of muscle development where genetically corrupted skeletal muscle progenitors fail to terminally differentiate. To understand RMS pathology, it is essential to understand the role of RMS genes in normal myogenesis. To determine genes of interest, our lab compared RMS core transcription factors (TFs), RMS essential genes, and genes overexpressed in our RMS genetically-engineered-mouse-models (GEMMs) and identified three TFs were represented: Pax7, MyoD1, and Sox8. PAX7 and MYOD1 play known roles in myogenesis and RMS, but the role of SOX8 in both processes remains unclear. My proposed project focuses on determining the role of SOX8 in myogenesis and rhabdomyosarcomagenesis. To determine the role of SOX8 in myogenesis I will perturb SOX8 in a primary myoblast culture system as well as in vivo through our novel Sox8Flox mouse. Preliminary data shows that SOX8 deficient myoblasts readily differentiate when not prompted, suggesting SOX8 is important for maintaining muscle stem cell fate. I will analyze the ability of SOX8 deficient and over-expressing muscle stem cells to pass through muscle differentiation to form functional muscle components. The second aspect of my project is to identify the role of SOX8 in RMS. I will utilize human RMS cells and our RMS GEMMs to dissect SOX8’s role in RMS tumorigenicity, tumor initiation, and transcriptional program through both loss-of-function and gain-of-function experiments. Finally, I will determine the SOX8 interactome in human RMS cells to gain mechanistic insight of SOX8 transcriptional regulation in human RMS. Understanding the role of SOX8 in myogenesis and RMS will increase our understanding of myogenic cell corruption and reveal the potential for core TFs to serve as therapeutic targets in RMS. St. Jude Children’s Research Hospital and the Hatley Lab fully support my training goals and will support my training plans to learn scientific techniques for my project, design rigorous and well-rounded experiments, scientific communication of my findings, and mentorship to those around me. The Hatley Lab expertise in RMS, GEMMs, and molecular biology will aid in my training goals. Additionally, the support garnered through the Core Facilities and Academic Programs Office at St. Jude Children’s Research Hospital will further support my ability to perform the proposed experiments and communicate the results effectively. The above combined with support from the Ruth L. Kirschtein Predoctoral Individual National Research Award (F31) will provide an excellent launching pad for my career goal to become an independent academic investigator.
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