Determining the Mechanism of Transformation for Rhabdomyosarcoma - ABSTRACT
Rhabdomyosarcoma (RMS) is an aggressive, soft-tissue sarcoma in children. While many clinical trials have
worked to improve patient outcomes, the 3-year survival rate for high-risk children hasn’t risen above 20% for
the past three decades. Children with RMS undergo surgery, radiation, and chemotherapy, which lead to serious
life-long consequences. RMS is thought to arise from a block in myogenesis which prevents normal skeletal
muscle development leading to tumor formation. However, RMS can develop in tissues devoid of skeletal muscle
such as the urinary bladder, prostate, and biliary tree, suggesting that RMS may have an alternative cell of origin
other than a myogenic progenitor. A recent publication by our lab, Drummond et al., identified endothelial cells
as a candidate cell of origin for RMS. Our genetically engineered mouse model expresses a constitutively active
Smoothened (SmoM2) allele in cells expressing Cre recombinase driven by the adipose protein 2 (aP2) promoter.
50% of these mice develop RMS specifically restricted to the neck by 28 days of life. aP2-Cre is expressed by
multiple cell types including endothelial cells, but not muscle cells. This indicates that RMS can arise from non-
myogenic cells, however many questions still remain. My proposed project focuses on understanding the role of
SmoM2 in tumorigenesis and proliferation, and the downstream signaling that causes a myogenic fate switch in
endothelial progenitors. To determine whether continued SmoM2 is required for tumor maintenance and
proliferation, I will culture tumor cells in vitro as tumor spheres and evaluate the ability of tumor spheres to
passage with SmoM2 knocked down. The second aspect of my project is to identify the mechanism of cellular
reprogramming leading to RMS formation specifically in the neck. Preliminary data from our lab, supported by
research from other groups, shows that head and neck muscle specification transcription factors such as Tbx1,
Pitx2, Tcf21 and Musculin are increased upon SmoM2 expression. To determine the mechanism of cellular
reprogramming initiated by SmoM2 expression in aP2-lineage cells, our lab generated a transgenic mouse that
conditionally overexpresses Tbx1 and acquired another that has conditional deletion of the Tbx1 allele, which
allows us to ascertain whether Tbx1 is sufficient and necessary to cause tumorigenesis. Understanding the
mechanistic basis for reprogramming in RMS will not only help us create more directed therapies for these
patients, but also suggests that similar reprogramming events may contribute to other solid tumors.
