Researchers at Baylor College of Medicine, Texas Children's Hospital, the Hospital for Sick Children in Toronto and collaborating institutions reveal in Nature Cell Biology a strategy that helps medulloblastoma, the most prevalent malignant brain tumor in children, spread and grow on the leptomeninges, the membranes surrounding the brain and spinal cord. They discovered a novel line of communication between metastatic medulloblastoma and leptomeningeal fibroblasts that mediates recruitment and reprogramming of the latter to support tumor growth. The findings suggest that disrupting this communication offers a potential opportunity to treat this devastating disease.
"Metastases, the spreading of a tumor away from its original site, are the most common and most important cause of illness and death for children with medulloblastoma," said co-first author Dr. Namal Abeysundara, a postdoctoral fellow who was working in the lab of Dr. Michael D. Taylor at the Arthur and Sonia Labatt Brain Tumor Research Center and the Developmental and Stem Cell Biology Program at the Hospital for Sick Children in Toronto, Canada during this project. Taylor, corresponding author of the work, is a professor of pediatrics, section of hematology-oncology, and of neurosurgery at Baylor, and is a staff neurosurgeon in the Department of Neurosurgery at Texas Children's Hospital.
In this study the researchers wanted to better understand how these tumors spread and grow on the leptomeninges as this could potentially help them develop better treatments to improve survival and quality of life for affected children.
The team took a closer look at metastatic medulloblastoma cells and fibroblasts in the leptomeninges. "We discovered previously unknown interactions in the leptomeninges that facilitate the spread and growth of medulloblastoma," Abeysundara said. "Metastatic medulloblastoma cells secrete a protein called PDGF that recruits leptomeningeal fibroblasts, which are then reprogrammed to become tumor-specific meningeal fibroblasts."
Reprogramed meningeal fibroblasts are distinct from normal fibroblasts; for instance, they support medulloblastoma growth by secreting BMP4 and BMP7, proteins that enhance tumor colonization and spread.
"We were most excited about the discovery of a novel intercellular communication cascade involving PDGF and BMP signaling," Abeysundara said. "We knew that the tumor cells and the non-tumor microenvironment cells must be communicating, it was encouraging to find at least one mechanism through which they do this. These findings shed light on how tumor and surrounding cells cooperate to create a supportive environment for leptomeningeal disease."
Furthermore, their discovery suggested that disrupting the interactions between metastatic tumor cells and the fibroblasts in the local microenvironment could prevent the progression of disease.
Indeed, the team found that blocking the PDGF signal from reaching the fibroblasts using a PDGF-R neutralizing antibody significantly improved survival in animal models. This finding supports the idea that targeting tumor-microenvironment communications could be a promising strategy for treating the human condition.
This study has implications beyond metastatic medulloblastoma. "Other cancers such as melanoma, breast and lung cancers also spread to the leptomeninges so the techniques and findings from this study may be applicable to a broader field," Abeysundara said.
"Our research uncovered a hidden communication network in the brain's protective layers that helps medulloblastoma spread. This novel discovery shows how tumor cells and non-tumor cells work together to create an environment that supports tumor growth, offering new insights into the complexity of medulloblastoma progression," said Taylor, the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at the Texas Children's Cancer and Hematology Center and a member of Baylor's Dan L Duncan Comprehensive Cancer Center. Learn more about the research conducted at Taylor lab by visiting their website.
For a complete list of authors, their affiliations and financial support for this study, see the publication.
