Skip to main content

Control of rhabdomyosarcoma cell identity provides clues to possible treatments

Findings from St. Jude Children’s Research Hospital show how control of transcription factors by a common tumor suppressor gene may provide a therapeutic opportunity in a type of childhood cancer.

Memphis, Tennessee, September 17, 2021

Two researchers stand outside while talking to each other.

First author Casey Langdon, Ph.D. (left), and corresponding author Mark Hatley, M.D., Ph.D., both of St. Jude Department of Oncology, revealed how the tumor suppressor gene PTEN plays a more important role in pediatric rhabdomyosarcoma than was previously appreciated.

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 was previously appreciated. The research highlights a possible new treatment approach. The study appears today in Nature Communications.

In this study, researchers showed that decreased expression of PTEN makes tumors more aggressive. The work also revealed that PTEN controls transcription factors such as PAX7 to govern rhabdomyosarcoma cell identity. Research findings also showed that loss of PAX7 was associated with tumor cell death, suggesting the protein as 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 younger than 10 years, 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 particular driver mutation.

“We're fundamentally interested in how normal developmental processes are hijacked to turn on cancer in children,” said corresponding author Mark Hatley, M.D., Ph.D., St. Jude Department of Oncology. “By knocking out Pten in our mouse model, we generated tumors that more faithfully recapitulate the rhabdomyosarcoma that kids get by introducing this abnormality that spans the majority of tumors.”

Transcription factors as a vulnerability for therapy

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

“When we looked in the tumor cells of our wildtype model, we found PTEN mostly in the nucleus, which is not where we expected it to be,” Hatley said. “That suggested to us that PTEN was contributing in 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 before been linked to cancer. They also found high expression of PAX7, which plays a known role in normal skeletal muscle development. They showed that PAX7 is involved in regulating and activating DBX1.

The researchers found that deleting Pax7 with Pten alters the cell’s identity, how a cell knows what it is and how to 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 PTEN loss maintains rhabdomyosarcoma cell identity.

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

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

These findings highlight how PAX7 may have a potential role as a molecular target for treating rhabdomyosarcoma as therapeutics-based transcription factors become available.

Other authors of the study are Katherine Gadek, Matthew Garcia, Myron Evans, Kristin Reed, Madeline Bush, Matthew Maguire, Patrick Leavey III, David Finkelstein, Hongjian Jin, Patrick Schreiner and Jerold Rehg of St. Jude; Jason Hanna, formerly of St. Jude and now of Purdue University, and Catherine Drummond, formerly of St. Jude and now of University of Otago.

The study was supported by grants from the National Cancer Institute (R01CA216344, R01CA251436, F31CA250398), the V Foundation for Cancer Research, The Rally Foundation for Childhood Cancer Research, Open Hands Overflowing Hearts, a Damon Runyon-Sohn Pediatric Cancer Fellowship and ALSAC, the fundraising and awareness organization of St. Jude.


St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit or follow St. Jude on social media at @stjuderesearch.