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 and cognitive impairment.

Sonic Hedgehog, one of the four biologically distinct subtypes of medulloblastoma, is named after the cellular pathway that is impaired in this cancer. The Sonic Hedgehog pathway is important for normal development of the brain, the central nervous system, eyes, limbs and other parts of the body; however, when the pathway goes awry in granule neurons in the cerebellum, cell proliferation spins out of control and cancer can develop. There are drugs directed at correcting the malfunctioning Sonic Hedgehog pathway that currently are in clinical trials, but sometimes, the tumor responds by presenting other mutations that allow it to continue growing. Additional treatments are much needed.

Dr. Tiemo Klisch, an assistant professor of molecular and human genetics and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, has been studying Sonic Hedgehog medulloblastoma for several years. His and other researchers' studies have increased our understanding of the regulation of the Sonic Hedgehog pathway and pointed at potential new strategies to treat this type of medulloblastoma.

How Sonic Hedgehog medulloblastoma can happen

"It is currently thought that when medulloblastoma develops, it recapitulates the embryonic developmental stages and pathways of the cerebellum," said Klisch, who is the corresponding author of this work. "I had been studying the role of transcription factor Atoh1 in normal cerebellar development for some time when I made the transition to studying its role in Sonic Hedgehog medulloblastoma."

Atoh1 is present in the cerebellum during normal embryonic development and up to three weeks after birth in mice, when the cerebellum has concluded its development. At this point, Atoh1 is no longer expressed in the cerebellum. In medulloblastoma, Atoh1 is re-expressed, and in concert with the activated sonic hedgehog pathway, leads to the development of this subtype of medulloblastoma.

"We also found that tyrosine 78 in Atoh1 is phosphorylated exclusively in 'tumor-initiating cells' in mice and in human samples of the Sonic Hedgehog subtype of medulloblastoma," Klisch said.

"Having tyrosine 78 in Atoh1 phosphorylated gives the tumor an advantage," said co-author Dr. Huda Zoghbi, professor of molecular and human genetics and of pediatrics and neuroscience at Baylor and director of the Jan and Dan Duncan Neurological Research Institute. "Phosphorylation increases Atoh1's activity, which enhances tumor growth in mice."

The researchers found that reducing the levels of Atoh1 promotes tumor regression in mice and provides a potential future strategy for treating this type of tumor.

"Because normal cerebellar cells around the tumor lack Atoh1, a potential treatment for Sonic Hedgehog medulloblastoma that is directed against Atoh1 would be expected to spare normal cells," Klisch said.

Furthermore, the researchers identified Jak2 as the enzyme that carries out most of the phosphorylation on tyrosine 78 on Atoh1, and determined that inhibiting Jak2 reduces Atoh1 phosphorylation and tumor growth in mice.

"Jak2 had not been implicated in medulloblastoma before," said Zoghbi, who also is an investigator at the Howard Hughes Medical Institute.

This study has provided new insights into the development of Sonic Hedgehog medulloblastoma and opens the possibility of new potential strategies to treat the disease in the future.
-end-
Read all the details of this study in the journal eLife.

Anna Vainshtein and Akash J. Patel also contributed to this work. The authors are affiliated with Baylor College of Medicine and/or the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Financial support for this work was provided by the Cancer Prevention and Research Institute of Texas (RP110390), the Christopher Getch Fellowship from the Congress of Neurological Surgeons, the Mary Alice Smith Charitable Foundation and the Howard Hughes Medical Institute. The project also was supported in part by the Intellectual and Developmental Disabilities Research Center grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Neurovisualization Core (D3 - Microscopy Core).

Baylor College of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.