Study helps explain launch switch for most common malignant pediatric brain tumor

March 29, 2018, UT Southwestern Medical Center
Grayscale immunofluorescence image of granule progenitor marker Pax6 of mouse embryonic day 16.5 cerebellum from conditional knockout of the G-protein-coupled receptor, Gpr161, arranged in a fourfold symmetric pattern (anterior to the left for bottom right image). Credit: Image constructed by Dr. Issei Shimada and Dr. John Shelton.

A delicate balance during brain development could have profound implications for understanding and treating medulloblastoma, the most common malignant brain tumor affecting children.

Medulloblastoma of the Sonic Hedgehog subtype can occur at any age, but it is most often seen in children. When not fatal, the disease is marked by severe neurocognitive disabilities. How Sonic Hedgehog subtype tumors develop has been poorly understood, said Dr. Saikat Mukhopadhyay, Assistant Professor of Cell Biology at UT Southwestern and senior author of a recent study featured on the cover of Cell Reports. By detailing the mechanisms underlying development of these tumors, these findings could lead to new treatments, noted Dr. Mukhopadhyay, a W.W. Caruth, Jr. Scholar in Biomedical Research.

Medulloblastomas originate in the cerebellum, an area at the skull's base that regulates motor control, posture, and balance. The Sonic Hedgehog subtype of medulloblastoma occurs when too many of a particular brain cell type—granule cells—are made. Granule cells make up most of the cerebellum and constitute as much as 80 percent of all brain neurons. During normal development, many granule cells are made when other nearby cells release the protein Sonic Hedgehog. However, some granule cells are made in the cerebellum even before Sonic Hedgehog is released, which led the researchers to investigate other factors that regulate early granule cell production.

"We modeled the Sonic Hedgehog in mice by deleting a gene for a G protein-coupled receptor called Gpr161 that was not known to be involved in this ," said first author Dr. Issei Shimada, Assistant Instructor in Cell Biology. "Interestingly, we found that in the absence of Gpr161, which actively represses the downstream pathway, the granule proliferate even before Sonic Hedgehog is secreted."

Dr. Mukhopadhyay added, "Repression of the downstream pathway in the absence of Sonic Hedgehog is as important as activation in its presence. Bottom line: The granule cell behaves like a car on a downhill slope with the hand brake on. Loss of the hand brake is as damaging as the accelerator being pressed too hard."

This means that Gpr161 acts as a for Sonic Hedgehog medulloblastomas by preventing too many from being made.

Medulloblastomas account for 15 to 20 percent of all pediatric brain tumors, according to the National Institutes of Health. While they are most commonly diagnosed in children between ages 3 and 8, they can be seen in all age groups. About 350 cases are diagnosed each year in the U.S.

In 2017, a survey of the National Cancer Database tracked 4,032 patients with medulloblastomas. Of these, 1,300 were age 18 or younger and received chemotherapy and radiation treatment. The median age was 8.4 years, and the group's five-year survival rate was 79 percent.

Only one drug, vismodegib, currently targets the upstream Sonic Hedgehog pathway for treating these pediatric tumors, Dr. Mukhopadhyay said. Now that this work has identified Gpr161 as a tumor suppressor, focusing on Gpr161 might be a new strategy to inhibit progression of tumors that develop resistance to drugs targeting the upstream Sonic Hedgehog pathway, he said.

Explore further: Atoh1, a potential Achilles' heel of Sonic Hedgehog medulloblastoma

More information: Issei S. Shimada et al. Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis, Cell Reports (2018). DOI: 10.1016/j.celrep.2018.01.018

Related Stories

Atoh1, a potential Achilles' heel of Sonic Hedgehog medulloblastoma

December 12, 2017
Medulloblastoma is the most common type of solid brain tumor in children. Current treatments offer limited success and may leave patients with severe neurological side effects, including psychiatric disorders, growth retardation ...

New pathway identified as a target for precision medicine against a common brain tumor

November 2, 2017
St. Jude Children's Research Hospital scientists have discovered a promising target for precision medicines to block a mechanism that drives several cancers, including about 30 percent of cases of the brain tumor called medulloblastoma. ...

Researchers identify a key controller of biological machinery in cell's 'antenna'

June 6, 2017
St. Jude Children's Research Hospital molecular biologists have identified an enzyme that activates and "supercharges" cellular machinery that controls how cells become specialized cells in the body.

Scientists create animal model for pediatric brain tumor

April 13, 2016
Sanford Research scientists are published in Nature Cell Biology for their work developing a model to explore therapies for a pediatric brain tumor known as choroid plexus carcinoma.

Sonic Hedgehog protein causes DNA damage and the development child brain tumors

October 14, 2014
Scientists at the IRCM and the University of Montreal discovered a mechanism that promotes the progression of medulloblastoma, the most common brain tumour found in children. The team, led by Frédéric Charron, PhD, found ...

Sonic Hedgehog protein causes DNA damage and the development of child brain tumours

October 29, 2014
Scientists at the IRCM and the University of Montreal discovered a mechanism that promotes the progression of medulloblastoma, the most common brain tumour found in children. The team, led by Frédéric Charron, PhD, found ...

Recommended for you

Potential seen for tailoring treatment for acute myeloid leukemia

December 8, 2018
Advances in rapid screening of leukemia cells for drug susceptibility and resistance are bringing scientists closer to patient-tailored treatment for acute myeloid leukemia (AML).

Study may offer doctors a more effective way to treat neuroblastoma

December 7, 2018
A very large team of researchers, mostly from multiple institutions across Germany, has found what might be a better way to treat patients with neuroblastoma, a type of cancer. In their paper published in the journal Science, ...

Inflammatory bowel disease linked to prostate cancer

December 7, 2018
Men with inflammatory bowel disease have four to five times higher risk of being diagnosed with prostate cancer, reports a 20-year study from Northwestern Medicine.

'Chemo brain' caused by malfunction in three types of brain cells, study finds

December 6, 2018
More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists ...

Scientists develop new technology for profiling unique genetic makeup of myeloma tumor cells

December 6, 2018
Cancer arises when cells lose control. Deciphering the "blueprint" of cancer cells—outlining how cancer cells hijack specific pathways for uncontrolled proliferation—will lead to more efficient ways to fight it. Joint ...

Putting the brakes on tumor stealth

December 6, 2018
New research undertaken at Monash University has shed new light on how some cancers are able to escape our immune system.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.