New research lays the foundation for more effective treatment of pediatric brain tumors

New research lays the foundation for more effective treatment of pediatric brain tumors

In a groundbreaking new study, scientists have uncovered the mechanisms of the blood-tumor barrier, one of the biggest obstacles to improving treatment effectiveness and preventing cancer cells from returning. The research team led by Dr. Xi Huang, senior scientist in the Developmental and Stem Cell Biology Program at the Hospital for Sick Children (SickKids), is laying the foundation for more effective treatment of medulloblastoma, the most common malignant pediatric brain tumor.

“Despite decades of research on brain tumors, the mechanisms that control the formation and function of the blood-tumor barrier remain poorly understood,” says Huang, who is also a senior researcher at the Arthur and Sonia Labatt Brain Tumor Research Center and the Canada Research Chair in Cancer Biophysics. “Our discoveries represent a breakthrough in understanding how the blood-tumor barrier forms and functions.”

In a paper published today in Neuron, the research team identifies a way to reduce the impact of the blood-tumor barrier on medulloblastoma treatment.

“Our research shows a way to overcome the blood-tumor barrier and treat devastating brain tumors in children more effectively.”

Reinterpretation of the blood-tumor barrier

The blood-brain barrier controls the extent to which molecules from our blood pass into the tissue of our brain - with the biological purpose of preventing harmful substances from entering the brain. However, this process also prevents more than 95 percent of small molecule drugs from reaching the brain, making treatment of brain diseases very difficult.

The barrier is formed in part by specialized cells that line the blood vessels in the central nervous system, called astrocytes.

Researchers have long thought that these astrocytes also form the blood-tumor barrier, which forms a similar barrier around brain tumor cells to prevent effective administration of chemotherapy. Huang and his team have now discovered that the blood-tumor barrier in medulloblastoma is a fundamentally new structure that is built by the tumor cells themselves.

Overcome barriers to treatment

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Huang's team, led by co-first authors Xin Chen, Ali Momin and Siyi Wanggou of SickKids, found that medulloblastoma tumor cells rely on the ion channel "Piezo2," a protein that plays an important role in cellular signaling to help form blood - tumor barrier. By genetically silencing Piezo2 in mice, medulloblastoma tumor cells were unable to form the blood-tumor barrier. Without this barrier, etoposide, a common chemotherapy drug, was better able to cross the blood-tumor barrier and treat the medulloblastoma tumor cells.

In addition to improving chemotherapy, the researchers also found that medulloblastoma tumor cells were significantly more sensitive to etoposide after silencing Piezo2.

Two major obstacles to the treatment of brain tumors are the blood-tumor barrier and a unique population of tumor cells that are inherently insensitive to chemotherapy. We found that turning off Piezo2 eliminates both barriers that can underlie treatment failure in patients.”

Dr. Xi Huang, Senior Scientist, Developmental and Stem Cell Biology Program, Hospital for Sick Children

“This research may not only reveal potential new avenues for providing effective therapies for pediatric brain cancer, but also stimulate re-examination of the blood-tumor barrier in other primary and metastatic brain tumors.”

Huang initiated this project seven years ago in his lab at SickKids, with other notable findings including how brain tumor cells hijack force-activated ion channels to promote tumor stiffening and growth.

Source:

The hospital for sick children

Reference:

Chen, X., et al. (2022) Mechanosensitive brain tumor cells establish a blood-tumor barrier to mask chemosensitivity. Neuron. doi.org/10.1016/j.neuron.2022.10.007.

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