PHILADELPHIA (July 22, 2020)—Researchers at Fox Chase Cancer Center have developed a new method for growing and storing medulloblastoma tumor cells, a step that could assist researchers in the development of new drugs. Stromal cells called astrocytes facilitate the signaling pathway that is associated with the formation of medulloblastoma, the most common type of malignant brain tumor found in children.
The hedgehog signaling pathway plays a significant role in the development of tumors. “We studied the mechanisms underlying medulloblastoma tumorigenesis and realized that one of the tumor stromal cells called an astrocyte has the main function of maintaining hedgehog signaling pathways in tumor cells, which is very critical for tumor cell proliferation,” said Zeng-jie Yang, MD, PhD.
Yang, one of the two leading authors on the study, is an associate professor in the Cancer Signaling and Epigenetics Program at Fox Chase who specializes in the study of medullobastoma. The other lead author is Edna Cukierman, PhD, also an associate professor in the same research program and co-director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute at Fox Chase. She specializes in 3D cultures that include tumor cells, non-tumor cells, and natural secreted support and signaling polymers of the tumor neighborhood known as the extracellular matrix. Yang and Cukierman collaborated on the study with researchers from Soochow University, Suzhou, China.
Astrocytes are a major part of the medulloblastoma microenvironment. They secrete the sonic hedgehog ligand and make up the extracellular matrix that supports tumor and surrounding cells, indicating a critical role for astrocytes in supporting the growth of medulloblastoma tumors.
Studying medulloblastoma has proven challenging because there are many obstacles to preserving these tumor samples after they are cultured, Yang said. “If you culture these tumor cells, eventually all the tumor cells will differentiate and permanently stop dividing. Moreover, the critical signaling pathway—the hedgehog pathway—is repressed in the inherent cultures,” he said.
“This is a big problem because it interferes with what we’re trying to do. We’re trying to develop a drug to repress hedgehog signaling in tumor cells and treat medulloblastoma, so these cultured tumor samples are not useful for our purposes.”
In the study, Yang and Cukierman teamed up to develop a method for medulloblastoma tumor cells to be cultured in the lab using a three-dimensional spheroid approach that both simulates their natural habitat in the brain and allows the cultures to be frozen for storage under optimal conditions. Through this method, medulloblastoma cells maintain the hedgehog signaling pathway activation, providing opportunities for researchers to study the formation of medulloblastoma tumors.
“We’ve provided a very useful tool for drug discovery, not only for our lab but for many labs studying medulloblastoma and other tumors,” said Yang. “The next steps are going to be that we start screening compounds for potential therapeutic effects to treat medulloblastoma.”
The study, "Sustained Hedgehog Signaling in Medulloblastoma Tumoroids is Attributed to Stromal Astrocytes and Astrocyte-Derived Extracellular Matrix," was published in Laboratory Investigation.