A new study from the Huang Lab reveals how fluid motion in the brain accelerates medulloblastoma spread

Researchers in the Department of Molecular Genetics at the University of Toronto have discovered that the natural flow of cerebrospinal fluid in the brain plays a critical role in driving the spread of medulloblastoma, the most common malignant brain tumour in children.

The paper, Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis, has been accepted in Nature Biomedical Engineering. It is led by recent MoGen PhD graduate Dr. Hyun-Kee Min in the Huang Lab.

As cerebrospinal fluid moves through the brain, it generates a physical force called fluid shear stress. The study shows that tumour cells are able to sense this force through a calcium-permeable ion channel on their surface. Once activated, the channel triggers a signalling cascade that strengthens the tumour cells’ ability to leave the primary site, survive in circulation, and metastasize throughout the brain and spinal cord.

One key part of this cascade is the Rho/ROCK pathway, a molecular switch that regulates how cells change shape and move. By linking the mechanical force of fluid flow to Rho/ROCK signalling, the study explains how medulloblastoma cells gain the ability to invade new areas. When the researchers blocked this pathway, either genetically or with a small molecule inhibitor, tumour spread was significantly reduced in pre-clinical models.

“Not only have we identified how tumour growth changes fluid flow in the brain and how the altered fluid motion impacts tumour cell behaviour, we also identified a small molecule that can target this fluidic force-dependent cascade with therapeutic potency,” says Dr. Xi Huang, Professor of Molecular Genetics at the University of Toronto.

The project also involved collaborations with Dr. Brian Ciruna and Dr. Madeline Hayes, both faculty members in Molecular Genetics, who contributed zebrafish modelling and imaging expertise. Together, the researchers carried out a three-species investigation using zebrafish, mouse, and patient samples, providing a comprehensive perspective on how physical forces influence tumour progression in the brain.

This discovery builds on Dr. Huang’s significant contributions to the study of pediatric brain tumours, including the development of “Lazy Piggy,” a genetic tool to identify cancer maintenance drivers, and the identification of potassium channels as key regulators of tumour growth. Taken together, his work continues to establish the Department of Molecular Genetics as a leader in cancer biology research.

The findings point to a targetable pathway that could guide the development of therapies aimed at halting metastasis in medulloblastoma, addressing one of the greatest clinical challenges in treating this cancer.