Rhabdomyosarcoma, a common form of soft tissue sarcoma in pediatric patients, can originate from aberrant development of nonmyogenic cells, according to research conducted at St. Jude Children’s Research Hospital.
Specifically, investigators showed that rhabdomyosarcoma originates from immature progenitors lining the blood vessels and hedgehog pathway activation. The blood vessels occupy the space between the muscle fibers that are found throughout the body, according to Mark E. Hatley, MD. Previously, researchers thought that this type of cancer was caused from immature muscle cells.
The endothelial cells were reprogramming themselves during early development to be more replicative of muscle cells with characteristics that drive the development of head and neck cancer, which explains why many cases of rhabdomyosarcoma occurs in the head and neck and why disease might occur in sites devoid of skeletal muscle, according to Hatley et al. Determining the origin of the cells could affect the survival and treatment of patients with this disease.
“Our muscle has stem cells that reside along our muscle fibers that are there to repopulate a muscle injury,” said Hatley. “Those muscle stem cells are called satellite cells and that has been hypothesized to be the cell of origin for this tumor.”
In an interview with OncLive
, Hatley, an assistant member of St. Jude Children’s Research Hospital and a corresponding author on the study, discussed the research of endothelial progenitor cells in pediatric patients with rhabdomyosarcoma and how it can lead to thorough analyses of the tumor cells.
OncLive: Please provide some background to this study.
Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Despite rigorous and well-planned clinical trials, the therapies and general outcomes have not changed much in the last 45 years. We are using the same chemotherapy that was used in 1971. Chemotherapy is the best therapy that we offer to these pediatric patients.
When you look at the tumors under the microscope or investigate a patient’s gene-expression profile, they seemingly resemble development of skeletal muscle. The thought has been that the tumors are transformed muscle progenitor cells. Our muscle has stem cells that reside along our muscle fibers that are there to repopulate a muscle injury. Those muscle stem cells are called satellite cells and that has been hypothesized to be the cell of origin for this tumor.
When you look at the children that have these tumors, one of the paradoxes is that they occur all over the body. That location is significant for their survival and subsequently how well they will respond to the treatment. The tumors can occur in places that have no skeletal muscle, such as the bladder, the salivary gland, the prostate, or the liver. Satellite cells or skeletal muscle progenitor cell origins do not explain the tumors that occur in those places.
What are the significant findings of this research?
This cancer cell shows that the tumors can come from a non-muscle cell. Different events, such as the activation of the hedgehog pathway in endothelial progenitor cells, can reprogram the cells to undergo a transdifferentiation event that makes them into a muscle-like cell. The tumors that we found in our model graphs were specifically located in the head and neck. Approximately 35% to 40% of the pediatric tumors occur in the head and neck.
We know that location matters for survival. The cell type that we showed was in the head and neck, but also throughout the mouth. However, only the cells in the head and neck transformed into tumors. It is likely that the origin of tumors outside of the head and neck are quite different. The cell of origin is a cell type that gets transformed and will add another layer of information onto where the location of the tumor is or the gene expression profile that could signify how to better classify the tumor. However, they may also identify novel pathways that were involved in the transformation that we could therapeutically target.
We identified that the muscle tumor comes from endothelial cells. Now that we understand the most common tumors in the patients, we can start further exploring both the development in the mouse models and tests for other genetic interactions to look for novel therapeutics.
What other remaining challenges in this patient population need to be addressed?
[One] of the biggest challenges in these patients is metastatic disease. Our model could determine how metastasis occurs. Our model doesn’t metastasize, but by combining other genetic changes, we could make the model more aggressive. Patients with rhabdomyosarcoma respond well to chemotherapy and radiation but after the completion of treatment, the tumor comes back and makes them a high-refractory population. We do not yet know the mechanisms for that resistance. We did preclinical trials in these mouse models where we tested some of these questions.
Are there any other ongoing studies in this population that you are excited about?
There is intense research in this area. A few years ago at St. Jude’s Children Research Hospital, we had a large effort called the Pediatric Cancer Genome Project where we performed whole-genome sequencing on the tumors and patients’ germline. We identified many of the different genetic [factors] in this tumor site. Building on that, we are using that information to build models that recapitulate other effects of the disease. The second phase of that project is ongoing, where we are investigating how epigenetic changes, such as histone modifications, DNA methylation, and chromosomal rearrangements, are contributing to the disease. We are spending a lot of effort on this tumor type.
Is there anything else that you would like to add?
The study was a serendipitous finding that this nonmuscle cell type was giving a tumor. This gave us the opportunity to find the cell of origin and where the tumors are coming from. By taking note of the oddity of the initial observation, we identified the cell of origin for one of the largest populations of these patients.
Drummond CJ, Hanna JA, Garcia MR, et al. Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from non-myogenic endothelial progenitors. Cancer Cell. 2018;33(1):108-124.e5. doi: 10.1016/j.ccell.2017.12.001.