Mark Hatley, MD, PhD, St. Jude Children’s Research Hospital

An Unexpected Cell of Origin for Embryonic Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a soft-tissue cancer that has features of skeletal (or striated) muscle. RMS is the most common type of sarcoma that arises in children and can be classified into two major subtypes: alveolar RMS and embryonal RMS. The genetic basis of alveolar RMS, the more aggressive disease, is well established; however, that of embryonal RMS, the more common form, is still poorly understood.

Treatment regimens for RMS include chemotherapy, radiotherapy, and surgery. Unfortunately, the overall survival of children with RMS has not significantly improved in 3 decades.

Mark E. Hatley, MD, PhD (Oncology), a physician-scientist in the Developmental Biology and Solid Tumor Program of the St. Jude Comprehensive Cancer Center, is working toward elucidating the molecular underpinnings of childhood RMS, with the ultimate goal of translating findings from preclinical models of the disease into the clinical setting. By increasing our understanding of the cellular origins of RMS, Dr. Hatley and his team hope to discover novel targets for the design and development of more effective therapeutic agents to treat the disease.

Embryonal RMS is thought to arise from striated muscle precursors because the tumor cells express the same genes (i.e., MyoD1, Myogenin, and Desmin) as do skeletal muscles. However, an origin restricted to muscle progenitors does not explain how RMS forms in locations that lack striated muscle, such as the salivary gland, prostate, urinary bladder, and liver.

Dr. Hatley and colleagues at the University of Texas Southwestern Medical Center (Dallas, TX) discovered that the developmental signaling pathway Sonic Hedgehog is deregulated in human embryonal RMS. In Cancer Cell, the researchers reported that perturbations of the Sonic Hedgehog pathway in genetically engineered mice can lead to embryonal RMS.

Tumors in these mutant mice closely resemble human embryonal RMS with respect to location, histology, and gene expression, making them an accurate model of the human disease. Remarkably, the cells that underwent malignant transformation were not muscle cells but adipose cells. Early-stage embryonal RMS tumor foci were surrounded by normal, nonneoplastic adipose tissue.

These findings provide new evidence that RMS may originate outside of the striated muscle lineage and give an initial explanation for how these tumors arise in tissues devoid of skeletal muscle.