NEW YORK – Researchers from Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center have identified a protein that activates brain stem cells to make new neurons – but that may be hijacked later in life to cause brain cancer in humans. The protein called Huwe1 normally functions to eliminate other unnecessary proteins and was found to act as a tumor suppressor in brain cancer.
These findings, published in the August 18 issue of Developmental Cell, were co-led by Antonio Iavarone, M.D., associate professor of neurology and pathology & cell biology and Anna Lasorella, M.D., assistant professor of pediatrics and pathology & cell biology, both of Columbia’s Institute for Cancer Genetics at the Herbert Irving Comprehensive Cancer Center.
“By identifying the normal function of Huwe1, we were able to learn that deregulation of Huwe1 function is involved in tumor development,” say Dr. Iavarone.
“This demonstrates that a gene’s basic function must be understood before we can learn how it also plays a role in the development of cancer,” says Dr. Lasorella.
During normal brain development, neural stem cells grow and divide rapidly before developing into neurons. To successfully change into neurons, they must remove all proteins that keep the cells in an immature, stem cell state. To understand how brain tumors develop, Drs. Iavarone’s and Lasorella’s teams decided that they needed to understand the development of normal neural stem cells. Their research demonstrated that Huwe1 is responsible for “crowd control” for the mechanism that regulates the stem cell mass in the developing brain – effectively weeding out unnecessary stem cell-specific proteins – and promoting neurogenesis. Without Huwe1, Dr. Lasorella discovered that in mice, too few mature neurons form in the brain, resulting in the brain failing to properly develop.
Because the stem cells and cancer cells share the capacity for rapid proliferation, but cancer cells have lost crowd control, Dr. Iavarone then looked for signs of Huwe1 alterations in human brain tumors. Compared to normal brain tissue, he found that Huwe1 activity in tumors was significantly lower than in normal brain tissue.
“The loss of Huwe1 may be an important factor in the development of brain cancer, suggesting that Huwe1 protein function may be used for new therapeutic targets to fight deadly brain cancer,” says Dr. Lasorella.
“Our next step will be to analyze the structural changes in Huwe1, and research ways to restore this gene in brain tumor patients,” says Dr. Iavarone. “In mice, giving Huwe1 back blocks the ability of normal stem cells to proliferate and develop tumors. We are hopeful that if we can restore Huwe1 activity in brain tumor cells resulting from Huwe1 deletion, then we can stop the tumor growth.”
Considering the relevance of the new findings, the paper has been selected for feature on the cover of this Aug. 18 issue of Developmental Cell, with the image below from the study on the cover. It shows the alterations of neural cells in the mouse brain carrying inactivation of Huwe1 with the superimposed molecular network responsible for those alterations. The network was assembled by the lab of research team member Andrea Califano, Ph.D., a computational biologist at Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center. The Califano lab developed computational algorithms to dissect transcriptional and post-transcriptional interaction that helped the team analyze the data – pinpointing the role of Huwe1. Dr. Califano is professor of biomedical informatics and founding director of Columbia’s new Systems Biology Initiative.
|NEUROGENESIS AND CANCER
The image shows a cortical section from the brain of E18.5 mouse embryo in which the gene coding for the Huwe1 ubiquitin ligase was selectively deleted. Inactivation of Huwe1 leads to expansion of the neural stem cell compartment (blue nuclei), disruption of laminar patterning (Tbr1, pink), and impaired generation of neurons (MAP2, green). Superimposed onto the cortical section is the neural N-Myc-DLL3 molecular network. The network is aberrantly activated and is responsible for the phenotypic abnormalities triggered by loss of Huwe1. The same molecular events (inactivation of Huwe1 and deregulation of N-Myc) are selected during oncogenic transformation in the human brain.
Image credit: Columbia University Medical Center
Brain tumors are among the most devastating cancers for both children and adults.
According to the American Brain Tumor Association, brain cancer is the leading cause of cancer-related death in patients younger than age 35. Approximately 17,000 people in the United States are diagnosed with brain cancer each year and nearly 13,000 die of the disease. The annual incidence of primary brain cancer in children is about 3 per 100,000.
Brain tumors do not discriminate. Primary brain tumors – those that begin in the brain and tend to stay in the brain – occur in people of all ages, but they are statistically more frequent in children and older adults. Metastatic brain tumors – those that begin as a cancer elsewhere in the body and spread to the brain – are more common in adults than in children.
Brain tumors are the most common of the solid tumors in children, and the leading cause of death from solid tumors. Brain tumors are the second leading cause of cancer-related deaths in children under the age of 20. Leukemia remains the first.
There are few effective treatments for brain tumors, which are typically very aggressive –necessitating high doses of chemotherapy, which may result in neuro-deficiencies and learning disabilities in patients.
This research was supported by grants from the National Cancer Institute of the National Institutes of Health (NIH), and by the National Centers for Biomedical Computing NIH Roadmap Initiative.
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The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital encompasses pre-clinical and clinical research, treatment, prevention and education efforts in cancer. The Cancer Center was initially funded by the NCI in 1972 and became a National Cancer Institute (NCI)–designated comprehensive cancer center in 1979. The designation recognizes the Center’s collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic and preventive approaches to cancer. For more information, visit www.hiccc.columbia.edu.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the most comprehensive medical research enterprise in New York City and state and one of the largest in the United States. Columbia University Medical Center is affiliated with NewYork-Presbyterian Hospital, the nation’s largest not-for-profit hospital provider. For more information, please visit www.cumc.columbia.edu.