From The Labs

A potential new therapeutic target for Group 3 medulloblastoma

The rhombic lip showing clusters of small blue embryonic cells nestled as rosettes around a conspicuous vascular structure in the cerebellar nodulus. Image courtesy of the authors/Cell, 2024.

Group 3 medulloblastoma (Gr3-MB) is one of the most aggressive forms of brain cancer in children and is associated with metastatic spread and poor survival. Looking to improve the outcomes of patients with this condition, a team of researchers at Baylor College of Medicine, Texas Children’s Hospital, the Hospital for Sick Children in Toronto and other collaborating institutions investigated the origin of this cancer. Their efforts led them to identify and locate a population of stem-like cells that initiates and maintains Gr3-MB in the developing brain. The study appeared in Cell.

Dr. Michael Taylor

“We believe that as Gr3-MB develops, it retains characteristics present in embryonic development, resulting in rapid tumor growth,” said corresponding author Dr. Michael D. Taylor, professor of pediatrics, hematology – oncology and neurosurgery at Baylor and Texas Children’s. He also is the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at Texas Children’s Cancer and Hematology Center. “Our goal was to identify embryonic cells that would give rise to tumors, as well as their location and factors that drive their growth.”

The researchers compared the genes expressed by Gr3-MB cells from six tumors with those expressed by normal human fetal hindbrain cells during the first trimester of pregnancy.

Dr. Abhirami Visvanathan

“We found trace of a lineage of embryonic stem-like cells in Gr3-MB tumors,” said first author Dr. Abhirami Visvanathan a postdoctoral fellow in the Taylor lab.

These cells express a protein called protogenin that is present only in these high risk Gr3-MB but absent in normal postnatal cerebellum.”

The researchers located the cancer stem-like cells in a specific brain region in the developing cerebellum called the rhombic lip. The cells are embedded in a structure unique to humans that is known as the interposed vascular plexus. When Gr3-MB tumors develop, they recreate the vascular plexus. Other types of medulloblastoma do not have this unique vascular structure.

“Stem-like cells in the tumor live in this immature blood vessel nest. Both tumor and vascular cells talk to each other and maintain a symbiotic niche benefiting both cells,” Visvanathan said.

A novel idea to treat Gr3-MB

The finding that the tumors have a small population of protogenin-expressing stem-like cancer cells that sustains their growth inspired the researchers to test a novel approach to treating GR3-MBs.

Instead of attacking the entire tumor, we hypothesized that eliminating the small population of cancer stem-like cells that sustains the tumor would be therapeutic, which is analogous to triggering the dissolution of an army by removing the leader,” Taylor said.

As predicted by the hypothesis, therapies directed at eliminating the cancer stem-like cells produced effective results in animal models. “We targeted the protogenin-expressing cells that sustain tumor growth with CAR T-cell immunotherapy. CAR T-cell therapy is a promising strategy in which immune T-cells are modified to attack a specific target – protogenin in this case – enabling them to kill the cancer,” Taylor said.

The researchers showed that eliminating the small population of stem-like cells present in Gr3-MB tumors led to tumor shrinkage in preclinical models. This exciting finding supports conducting further investigations to determine whether this strategy is effective in treating human Gr3-MB.

The study also shows that targeting the vascular niche that supports tumor cell growth is another potential therapeutic option. Further studies are needed to explore this possibility.

See the complete list of authors, their affiliations and the financial support for this work in the publication.

 

By Ana María Rodríguez, Ph.D.

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