Research reveals a possible new treatment approach for pediatric rhabdomyosarcoma

Scientists at St. Jude Children’s Research Hospital have revealed how the tumor suppressor gene PTEN plays a more important role in pediatric rhabdomyosarcoma than previously believed. The study highlights a possible new treatment approach. The study appears today in Nature Communications.

In this study, researchers showed that reduced expression of PTEN makes tumors more aggressive. The work also revealed that PTEN controls transcription factors such as PAX7 to regulate the identity of rhabdomyosarcoma cells. Study results also showed that loss of PAX7 was associated with tumor cell death, suggesting the protein is a potential treatment target.

Rhabdomyosarcoma is a type of soft tissue cancer that resembles skeletal muscle. It is the most common type of soft tissue sarcoma in children. Most cases of rhabdomyosarcoma occur in children under 10 years of age, and some children are even born with it.

Rhabdomyosarcoma either has a fusion oncoprotein (when two genes come together abnormally and create problematic proteins) with PAX3-FOXO1 or PAX7-FOXO1 or is fusion negative. Fusion-negative rhabdomyosarcoma is genetically diverse and sequencing has not found a specific driver mutation.

We are fundamentally interested in how normal developmental processes are hijacked to fuel cancer in children. By knocking out Pten in our mouse model, we have generated tumors that more faithfully recapitulate the rhabdomyosarcoma that children have by introducing this abnormality that encompasses most tumors.”

Mark Hatley, MD, Ph.D., Corresponding Author, St. Jude Department of Oncology

Transcription factors as vulnerability to therapy

By looking at methylation data, how much (or little) certain genes are expressed, research by others found that reduced expression of the tumor suppressor gene PTEN is common in fusion-negative rhabdomyosarcoma.

“When we looked in the tumor cells of our wild-type model, we mostly found PTEN in the nucleus, which is not where we expected it,” Hatley said. “That suggested to us that PTEN contributed to transcriptional control and gene regulation.”

Hatley and his team focused on the relationship between PTEN and two transcription factors – DBX1 and PAX7. The researchers found high expression of DBX1, which has never been linked to cancer before. They also found high expression of PAX7, which has a known role in normal skeletal muscle development. They showed that PAX7 is involved in regulating and activating DBX1.

The researchers found that removing Pax7 with Pten changes the cell’s identity, how a cell knows what it is and how it should behave. Scientists observed a change in cells from skeletal muscle to smooth muscle.

The findings show that in addition to PTEN loss causing a more aggressive tumor, enhancing PAX7 expression maintains PTEN loss in rhabdomyosarcoma cell identity.

“This work demonstrates how genetically modified mouse models can provide insight into how different tumor suppressors may alter the dynamics of tumor initiation,” said first author Casey Langdon, Ph.D., St. Jude Department of Oncology. “Our findings show that not only is PTEN in the nucleus controlling gene expression, it actually dictates tumor cell fate in rhabdomyosarcoma. It is critical for maintaining tumor cell identity.”

“When we looked at human rhabdomyosarcoma cells and took PAX7 out, the cells died,” Langdon added. “This PTEN-PAX7 relationship is completely required to sustain their existence.”

These findings highlight how PAX7 may have a potential role as a molecular target for the treatment of rhabdomyosarcoma as therapy-based transcription factors become available.


St. Jude Children’s Research Hospital

Reference magazine:

Langdon, CG, et al. (2021) Synthetic essentiality between PTEN and core dependency factor PAX7 dictates the identity of rhabdomyosarcoma. Nature Communication.

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