New research rethinks the blood-tumour barrier and identifies novel path to brain cancer treatment
In a ground-breaking new study, scientists have uncovered the mechanics of the blood-tumour barrier, one of the most significant obstacles to improving treatment efficacy and preventing the return of cancerous cells.
The research team, led by Dr. Xi Huang, a Senior Scientist in Developmental & Stem Cell Biology program at The Hospital for Sick Children (SickKids), lays the foundation for more effectively treating medulloblastoma, the most common malignant paediatric brain tumour.
“Despite decades of research on brain cancer, the mechanisms that govern the formation and function of the blood-tumour barrier have remained poorly understood,” says Huang, who is also a Principal Investigator at the Arthur and Sonia Labatt Brain Tumour Research Centre and Canada Research Chair in Cancer Biophysics. “Our discoveries represent a breakthrough in the understanding of how the blood-tumor barrier forms and works.”
In a paper published today in Neuron, the research team identifies a way to reduce the impact of the blood-tumour barrier on medulloblastoma treatment.
Reimagining the blood-tumour barrier
The blood-brain barrier controls to what extent molecules in our blood enter the tissue in our brain - with the biological purpose of preventing harmful agents from being spread to the brain. However, this process also prevents more than 95 per cent of small molecule drugs from entering the brain, making conditions of the brain very difficult to treat.
The barrier is formed in part by specialized cells that tile the blood vessels in the central nervous system, called astrocytes.
Researchers have long thought that these astrocytes also comprise the blood-tumour barrier, which forms a similar barrier around brain tumour cells to prevent effective delivery of chemotherapy. Huang and his team have now identified that the blood-tumour barrier in medulloblastoma is a fundamentally new structure constructed by the tumour cells themselves.
Artistic rendering of cancer cell ensheathment on blood vessels. Created by Siqi Ou using Midjourney.
Breaking the barriers to treatment
Huang’s team, led by co-first authors Xin Chen, Ali Momin and Siyi Wanggou at SickKids, found that medulloblastoma tumour cells depend on the ion channel ‘Piezo2,’ a protein that plays an important role in cellular signaling, to help form the blood-tumour barrier. By genetically silencing Piezo2 in mice, medulloblastoma tumour cells were unable to form the blood-tumour barrier. Without this barrier, etoposide, a common chemotherapy medication, was better able to cross the blood-tumour barrier and treat the medulloblastoma tumour cells.
In addition to improving the delivery of chemotherapy, the researchers also found that medulloblastoma tumour cells are significantly more sensitive to etoposide after silencing Piezo2. “Two major obstacles in brain cancer treatment are the blood-tumour barrier and a unique population of tumour cells that are intrinsically insensitive to chemotherapy. We found that knocking out Piezo2 addresses both obstacles that can underlie therapy failures in patients,” says Huang.
“This research may not only inform potential new ways to deliver effective therapies for paediatric brain cancer, but also inspire renewed investigation into the blood-tumour barrier in other primary and metastatic brain tumours.”
Huang initiated this project seven years ago in his lab at SickKids, with other notable findings including how brain tumour cells hijack force-activated ion channels to promote tumour stiffening and growth.
This study was supported by the Arthur and Sonia Labatt Brain Tumour Research Centre, Garron Family Cancer Centre, Sontag Foundation, Cancer Research Society, Canadian Cancer Society, b.r.a.i.n.child, Meagan’s HUG, Ontario Early Researcher Award, American Brain Tumor Association Discovery Grant, Natural Sciences and Engineering Research Council (NSERC) Discovery Grant, Ontario Institute for Cancer Research (OICR) Brain Cancer Translational Research Initiative, Canadian Institutes of Health Research (CIHR) Project Grants and SickKids Foundation.