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 tumour 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 tumour growth.

The findings suggest that disrupting this communication offers a potential opportunity to treat this devastating disease.

“Metastases, the spreading of a tumour 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 Tumour Research Centre and the Developmental and Stem Cell Biology Programme at the Hospital for Sick Children in Toronto, Canada during this project.

Taylor, corresponding author of the work, is a professor of paediatrics, section of haematology-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 tumours 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 tumour-specific meningeal fibroblasts.”

Reprogrammed meningeal fibroblasts are distinct from normal fibroblasts; for instance, they support medulloblastoma growth by secreting BMP4 and BMP7, proteins that enhance tumour colonisation and spread.

“We were most excited about the discovery of a novel intercellular communication cascade involving PDGF and BMP signalling,” Abeysundara said.

“We knew that the tumour cells and the non-tumour 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 tumour and surrounding cells cooperate to create a supportive environment for leptomeningeal disease.”

Furthermore, their discovery suggested that disrupting the interactions between metastatic tumour 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 neutralising antibody significantly improved survival in animal models.

This finding supports the idea that targeting tumour-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 tumour cells and non-tumour cells work together to create an environment that supports tumour growth, offering new insights into the complexity of medulloblastoma progression,” said Taylor, the Cyvia and Melvyn Wolff Chair of Paediatric Neuro-Oncology at the Texas Children's Cancer and Haematology Centre and a member of Baylor’s Dan L Duncan Comprehensive Cancer Centre.

Source: Baylor College of Medicine