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Developmental biology - Brain Disorders

Found, switch for most common pediatric brain tumor

A delicate balance in brain development could explain development of and treatment for medulloblastoma...


New research from the University of Texas Southwestern Medical Center explains how 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, explains Dr. Saikat Mukhopadhyay MD PhD, 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.

Medulloblastomas originate in the cerebellum, an area at the base of the skull that regulates motor control, posture, and balance. The Sonic Hedgehog subtype of medulloblastoma occurs when too many granule brain 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 upon the release of the protein Sonic Hedgehog. However, some granule cells are made in the cerebellum even before Sonic Hedgehog is released, which led researchers to investigate factors that regulate early granule cell production.
"We modeled the Sonic Hedgehog medulloblastoma in mice by deleting a gene for G protein-coupled receptor called Gpr161 not known to be involved in this tumor. Interestingly, we found that in the absence of Gpr161, which actively represses the downstream pathway, granule cells proliferate even before Sonic Hedgehog is secreted."

Issei Shimada PhD, Assistant Instructor, Cell Biology, UT Southwestern Medical Center and first author on the paper.

Dr. Mukhopadhyay adds: "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 is a tumor suppressor for Sonic Hedgehog medulloblastomas preventing too many granule cells 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. Their median age was 8.4 years, with a five-year survival rate of 79 percent.

According to Mukhopadhyay, only the drug vismodegib currently targets the upstream Sonic Hedgehog pathway and is used to treat this class of pediatric tumor. Now that Gpr161 is identified as a tumor suppressor, focusing on it might be a new way to inhibit progression of tumors resistant to drugs targeting the upstream Sonic Hedgehog pathway.

Highlights
Gpr161 is a tumor suppressor in sonic hedgehog (Shh) subtype medulloblastoma (MB)
Granule cell (GC) progenitor production increased upon Gpr161 deletion and was cilium dependent
Gpr161 restricted premature Shh pathway activity and GC progenitor overproduction in embryos
Reduced GPR161 expression correlated with poor survival of SHH-MB patients.

Summary
Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein-coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis from Gpr161 deletion was cilium dependent, unlike normal development. Low GPR161expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis.

Authors: Issei S. Shimada, Sun-Hee Hwang, Bandarigoda N. Somatilaka, Xin Wang, Patryk Skowron, Jiwoong Kim, Min Kim, John M. Shelton, Veena Rajaram, Zhenyu Xuan, Michael D. Taylor, Saikat Mukhopadhyay.


About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.


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Apr 4, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Immunofluorescence image of granule progenitor marker Pax6 in mouse embryo day 16.5, of cerebellum after conditional knockout of Gpr161. Mouse brain is arranged in a fourfold symmetric pattern (anterior to the left of bottom right image). Image constructed by Dr. Issei Shimada and Dr. John Shelton.


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