New tumor models provide insights into deadly sarcomas

Sarcomas are highly metastatic soft tissue and bone cancers that are often difficult to treat. Scientists have struggled to study these cancers because they lack good research models. But that could change, thanks to new research from researchers at the UC Davis Comprehensive Cancer Center and UCLA Health Jonsson Comprehensive Cancer Center.

In a study published in the journal Clinical research on cancerThe researchers said they manipulated mesenchymal stem cells to create four different models of sarcoma. This versatile platform has already identified potential therapeutic targets and could eventually lead to new treatments.

“I’m excited about this model because we can take the same starting material, mesenchymal stem cells, and turn them into four different types of sarcomas,” said Janai Carr-Ascher, assistant professor in the Division of Hematology and Oncology and senior author of the study.

“This gives us an incredible tool, allowing us, for the first time, to understand the similarities and differences between these tumors, to learn how they grow, evolve and metastasize.”

In this highly collaborative effort, Carr-Ascher worked closely with Thomas Graeber, professor of molecular and medical pharmacology at UCLA’s Broad Stem Cell Research Center, and others in his lab, including graduate student Jack Freeland. He and UC Davis graduate student Maria Muñoz were co-senior authors.

Sarcomas are difficult to treat because they are often diagnosed late and are extremely diverse: there are about 70 different types. On the other hand, there are very few sarcoma models to study. The most common sarcomas behave radically differently, and because they are so poorly understood, clinicians have been limited to just a few therapies. Carr-Ascher and her colleagues believe these new models could help generate more precise treatment options.

“Once we understand the differences that drive some cells to bone cancer and others to various soft tissue cancers, we can start to study the disease,” Carr-Ascher said. “Hopefully, once we know how it’s made, we can figure out how to break it down.”

Mesenchymal stem cells are primitive cells that differentiate into bone, cartilage, muscle, and fat. In 2017, Carr-Ascher and her colleagues began studying the genetic signals that influence mesenchymal cells to transform into different sarcomas.

The team began using sarcoma data from the Cancer Genome Atlas. They found that two well-known oncogenes (YAP1 and KRAS) drive mesenchymal cells to undifferentiated pleomorphic sarcoma and myxofibrosarcoma, two of the most common soft tissue cancers in adults. Two other oncogenes (CDK4 and PIK3CA) drive leiomyosarcoma (smooth muscle cancer) and osteosarcoma (bone cancer), although less consistently.

These results underscore the versatility of the model. While it is not easy to identify the genetic signals that differentiate a mesenchymal stem cell into a specific sarcoma, this model provides a template to test the role of different proteins in this process. Once the appropriate oncogenes are identified, it takes scientists about a week to create the viral delivery system that integrates them into stem cells. With this technology, researchers can potentially create models for many, if not all, sarcomas.

To take the research further, the team treated YAP1 tumors with existing anticancer agents, which reduced cell viability. Ultimately, these models could become indispensable tools to help develop more advanced anti-sarcoma therapies.

“We were able to take our model, superimpose it on human disease, and use that analysis to identify new therapies to test,” Graeber said.

“Furthermore, these models are genomically unstable, just like human sarcomas, and understanding why their genomes are so unstable is a key topic in sarcoma research. Increased genomic instability has been linked to aggressive tumor growth and drug resistance, and this is an area where we need to make progress.”

The team will continue to study these new sarcoma models. They are particularly interested in the mechanisms that promote metastasis. In addition, there may be other existing therapies that could be repurposed to treat sarcomas.

“Based on these data and what we saw in The Cancer Genome Atlas, we believe that YAP1, which is part of a key signaling pathway, is extremely important in sarcomas,” Carr-Ascher said.

“Related inhibitors are currently in clinical trials for other tumor types. If we can demonstrate the importance of this pathway and identify useful combination therapies, this could have a major translational impact.”