Rhabdomyosarcoma is a rare childhood cancer that arises in muscle stem cells. Between 250-350 cases are treated each year. The disease most commonly begins as a noticeable swelling in the arms, legs, head, neck, or groin, and is treated by surgical removal of the tumor, as well as chemotherapy or irradiation. Currently, about 80% of patients diagnosed with rhabdomyosarcoma survive, as the disease is often caught early enough for intervention.

In this feature, one senior investigator, one junior investigator, and one postdoctoral researcher—all working at the Harvard Stem Cell Institute—share recent findings that could lead to safer treatments for young cancer patients.

Studying Rhabdomyosarcoma in Zebrafish: HSCI Executive Committee Chair Leonard Zon, MD

For pediatric oncologist Leonard Zon, MD, the fact that rhabdomyosarcoma is a rare cancer doesn’t change the need for new treatments. Physicians try to avoid radiation-based therapies in children because of the long-term effects, such as developing another type of cancer later in life. His laboratory hopes to identify clinical alternatives that could slow tumor growth, or kill the cancer cells entirely, without the need of radiation.

Zon’s search for therapies takes place in the zebrafish, which under certain conditions develop tumors very similar to human rhabdomyosarcoma. “One of the things that’s really interesting in zebrafish is that the embryos are completely transparent and you can watch the tumors invade the normal tissues,” he said. “That’s a process that you can’t study in any other organism.”

Zon, chair of the HSCI’s Executive Committee and the director of the Stem Cell Program at Boston Children’s Hospital, is the first scientist to successfully apply basic research from the zebrafish to develop an FDA-approved, human cancer treatment (for melanoma). He now hopes to make a similar translation for rhabdomyosarcoma patients and already has several leads.

Interested in learning what types of genes could transform a muscle stem cell into a malignant tumor, Zon’s postdoctoral fellow Narie Storer, MD, PhD, studied promoters of gene expression that are key for muscle stem cell differentiation. She found promoters functioning during early muscle development could be linked to the RAS oncogene, and this caused a more malignant cancer and poorer zebrafish survival than when RAS was driven by later muscle promoters. This basic biological insight could help doctors better predict how aggressive a patient’s rhabdomyosarcoma might be.

Another line of research, led by postdoctoral fellow Colleen Albacker, PhD, searched for factors that might suppress the development of rhabdomyosarcoma tumors. The team looked specifically at epigenetic regulators—genes that control the way DNA is folded in the nucleus so that each cell type only expresses the genes that are necessary. The researchers identified one gene, called SUV39H1, which was able to prevent the cancer cells from dividing.  

“It stops the cells dead, right at the very beginning of these tumors,” Zon said. “So it’s very exciting research and we’re hoping that it will translate into the clinic.”

Research Cited:

Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis. Development. July 15, 2013.

The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish. PLOS One. May 21, 2013.

Identifying the Cause of Rhabdomyosarcoma: HSCI Principal Faculty Member David Langenau, PhD

Research scientist David Langenau, PhD, stumbled upon the fastest model of cancer development currently in existence while a postdoctoral fellow in the Zon Laboratory. Using a piece of DNA that should have produced leukemia, zebrafish remarkably developed rhabdomyosarcoma by just 10 days of life. This resulted from misexpression of the targeted RAS oncogene within muscle stem cells. “Despite not being the initial type of childhood cancer we sought to model, we knew studying this fast-growing tumor was going to be important to understanding human disease,” he said.

In 2012, Langenau, who now has his own laboratory at Massachusetts General Hospital, took advantage of the zebrafish’s transparency to image the birth of rhabdomyosarcoma. “We were able to visualize the first cells to initiate cancer and document when vasculature is recruited to the growing tumor,” he said. Using a combination of fluorescent proteins and transgenic fish, his team was also able to determine that it was not the stem cells within the tumors that first become metastatic, but the cells that they differentiate into.

The finding helped reframe rhabdomyosarcoma as a cancer that affects a few hundred children a year into a model disease that can be broadly applied to other stem cell cancers. “It’s not the stem cells that drive local infiltration and metastasis,” Langenau said. “Rather, there are unique cell types that lead the charge and cause the cancers to migrate. This concept of division of labor between defined cancer cell types is novel and will likely be important for our understanding of cancer in general,” he added.

His most recent investigation into the origins of rhabdomyosarcoma concerned the genetic changes that cause cancer. Zebrafish acquire mutations in significantly smaller segments of their genetic material—in regions of 3 to 10 genes compared to regions of 100 or more genes in humans. The level of complexity in humans makes it challenging to identify specific mutations that drive cancer growth, but the simplicity of the zebrafish allowed Langenau’s postdoctoral fellow Eleanor Chen, MD, PhD, to lead a cross-species genomic comparison to discover 18 genes that play a role in both zebrafish and human rhabdomyosarcoma tumor development.

Langenau noted, “Zebrafish have proven to be powerful screening tool to identify genetic changes that drive cancer growth. The key is to now translate our findings from fish to  human and mouse disease.”

Research Cited:

Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLOS Genetics. August 29, 2013

In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell. May 15, 2012

Is Rhabdomyosarcoma the Right Diagnosis?: HSCI Postdoctoral Fellow Simone Hettmer, MD

Families fear the worst when they make an appointment with Simone Hettmer, MD, a pediatric oncologist at the Dana-Farber Cancer Institute’s Jimmy Fund Clinic. Patients are referred to her when they are suspected to have a soft tissue cancer—such as in the bone, cartilage, or muscle. On several occasions, Hettmer has needed to tell parents that their child has rhabdomyosarcoma.

“In a way, it’s just a label, and it’s very important that families know what that label is,” she said. “The actually day-to-day situation of dealing with what’s going on, at the time, can be quite overwhelming.”

The treatment for rhabdomyosarcoma is very aggressive. The multiple clinic and hospital visits are a strain on families. However, surprising new research by Hettmer may relieve at least a handful of families of this burden by changing the diagnosis of rhabdomyosarcoma to rhabdomyoma, a benign tumor that can be removed by surgery.

In addition to her work with patients, Hettmer is a postdoctoral fellow in the Joslin Diabetes Center laboratory of HSCI Executive Committee member Amy Wagers, PhD.

In the lab, Hettmer uses mouse models to study cancer formation and behavior. While studying a type of rhabdomyosarcoma tumor caused by a mutation in the key cell division pathway, sonic hedgehog, she noticed the tumors were far less aggressive than normal.

“There were unusual aspects about the way these tumors acted,” Hettmer said. “I reviewed the tumors with a human pathologist and they didn’t look like a typical high grade rhabdomyosarcoma, but more like a very rare benign tumor called fetal rhabdomyoma.”

Hettmer then wanted to know whether the mutation that caused this type of tumor in mice could be found in human cancers. She examined different rhabdomyosarcoma tumor samples that had been removed from Boston-area patients, and ultimately found five that were caused by a mutation in the sonic Hedgehog pathway.

“It’s pretty clear that rhabdomyosarcoma is not just one cancer, but many related cancers,” Hettmer said. “What I’m hoping to achieve is to tease apart little subgroups and then find a way to identify them reliably, and then figure out what we need to do to actually fix them.”

She has already obtained access to human rhabdomyosarcoma samples to directly follow up on the hypotheses generated by her work.

Research Cited:

Mutations in Hedgehog pathway genes in fetal rhabdomyomas. Journal of Pathology. August 6, 2013