Long believed to arise from immature muscle cells, rhabdomyosarcoma (RMS) appears to have a different origin.
New research from St Jude Children’s Research Hospital in Memphis, Tennessee, shows that rather than originating within muscle, the disease appears to begin with the immature progenitors that would normally develop into cells lining blood vessels.
While these data are early and preclinical, they could have therapeutic implications in the future.
Lead author, Mark Hatley, MD, PhD, from the Department of Oncology, noted that understanding the cell of origin will bring much-needed insights into improving diagnosis and treatment of rhabdomyosarcoma.
A better understanding of the machinery of rhabdomyosarcoma could enable entirely new treatment approaches.
“We are still using the same chemotherapy that was in use 46 years ago, with the same outcomes,” Dr Hatley said. “A better understanding of the machinery of rhabdomyosarcoma could enable entirely new treatment approaches.”
The study was published in the January 8 issue of Cancer Cell.
RMS is the most common soft tissue sarcoma in children, but prognosis varies. Overall survival is more than 80% in patients with localized disease who receive standard treatment with surgery, radiation therapy, and chemotherapy. But the outlook for those with metastatic disease is substantially worse, with a 5-year, event-free survival rate of less than 30%.
The authors note that despite decades of intensive clinical trials, survival and treatment options have not improved for the high-risk patients. Thus, a better understanding of tumor origin could help in the development of better therapies.
A “Serendipitous” Moment
In an interview with Medscape Medical News, Dr Hatley explained that his team had tried to model RMS by using traditional methods, such as by trying to activate oncogenes and delete tumor suppressors in skeletal muscle type cells. “And while I was doing all the typical things that one would do in trying to model RMS, a colleague at UT Southwestern made a rather serendipitous finding,” said Dr Hatley. “He was studying adipose development and was investigating the hedgehog pathway, and was curious how it was involved in adipose tissue development.”
Jonathan Graff, MD, PhD, a professor of developmental biology, used a mouse model to activate the hedgehog pathway in adipose cells in order to study how it might affect the development of fat tissue. To his surprise, all of the mice developed RMS, said Dr. Hatley. “And it was at a ‘mouse timepoint’ which coincided with the age when most children will develop RMS.”
About 40% of children develop tumors in the head and neck; in this mouse model, the tumors were specifically located in the head and neck.
Dr Graff was not interested in pursuing this line of discovery as he wasn’t a cancer biologist, explained Dr Hatley, “So we collaborated, and I championed the model.”
At the same time, some evidence also suggested that there were common progenitor cells between adipose and skeletal muscle cells, with the adipose tissue known as “brown adipose.” The function of brown adipose tissue is to transfer energy from food into heat.
Dr Hatley hypothesized that this was going to turn out to be the origin of the tumor; that the activated hedgehog pathway in the fat cells was converting them into a muscle-like tumor.
Continuing his research at St Jude’s, and trying to determine the origin of RMS, Dr Hatley had another huge surprise. “It turned out that they weren’t fat cells at all but were endothelial cells that make up the blood vessels that course between the muscle fibers,” he said. “And when we activate the hedgehog pathway in the early development of these cells, it activates transcription factors that are involved in the specification and setting up of the skeletal muscles—especially those in the head and neck.”
He explained that they were able to follow the cells through tumor development, purify them, and then show that the genes being regulated were in fact those that were important in establishing head and neck muscle.
By activating the hedgehog pathway, Dr Hatley and his colleagues showed that RMS originates from endothelial progenitor cells that are specifically located in the head and neck. They also demonstrated how normal muscle development is disrupted and drives location-specific tumor formation through transdifferentiation—which is induced by hedgehog activation in endothelial progenitors.
Impact of the Discovery
Their research has several immediate implications, he pointed out.
RMS, along with other rare pediatric diseases, has been classified by “the way they look under the microscope.”
“Just as we’ve done with large-scale genomic studies, we have begun to be able to parse these diseases into different subgroups,” he said. “And it turns out that they behave differently and have a different response to chemotherapy. With RMS, one of the things that has borne out in the last 40 years is that tumor location is critical in prognosis.”
This study also shows and suggests that there are many cells of origin and that this isn’t one disease but many diseases. “The tumors we see in head and neck may have a different cell of origin, and this sets up the likelihood of who will or will not respond to treatment,” Dr Hatley said. “This can help us refine our classification strategy and understand origins of the tumor.”
While the tumor model that they are now studying doesn’t present targets for new drugs, if the mechanism controlling that model can be identified, it may yield therapeutic drug targets in the future.
The findings may also lead to actually preventing RMS in children with a genetic predisposition to the cancer. But for now, “it can help us refine our preclinical model systems so that we are testing therapeutics in the most representative context, and that will be the most immediate impact of the study,” Dr Hatley added.
The research was supported by the V Foundation for Cancer Research, grants from the National Institutes of Health, and ALSAC, the fundraising and awareness organization of St Jude. The authors have disclosed no relevant financial relationships.
Cancer Cell. 2018;33:108-124. Abstract
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