NF Center Trainee Publishes Groundbreaking Study on the Origins of NF1 Optic Gliomas

Dr. Nicole Brossier, Instructor in the Division of Pediatric Hematology and Oncology at St. Louis Children’s Hospital, recently reported that numerous factors explain why children with NF1 develop optic gliomas.

In her study, Dr. Brossier, who is a pediatric neuro-oncologist specializing in the care of children with NF1-associated brain tumors, showed that the cells which likely give rise to optic gliomas in mice with Nf1 mutations exhibit different capacities to grow as a function of the type of germline Nf1 gene mutation, the age of the mouse, and the location of the cells in the brain. Her detailed work demonstrates that Nf1 brain tumor formation in mice must occur during embryonic development, in specific progenitor cells in the brain, and in mice with some, but not all, germline Nf1 gene mutations.

This exciting report was recently published in Neuro-Oncology. Future studies by Dr. Brossier will focus on examining risk factors that underlie brain tumor formation in children.


Brossier NM, Thondapu S, Cobb OM, Dahiya S, Gutmann DH. Temporal, spatial, and genetic constraints contribute to the patterning and penetrance of murine Neurofibromatosis-1 optic glioma. Neuro Oncol. 2020 Oct 20:noaa237. doi: 10.1093/neuonc/noaa237. Online ahead of print. PMID: 33080011

 

Alexander Chen awarded Training Grant from the Center of Regenerative Medicine

Alexander Chen, PhD, a postdoctoral fellow in the Gutmann Laboratory, was recently awarded a “Training in Regenerative Medicine” training grant (T32) from the National Institute of Biomedical Imaging and Bioengineering. This program aims to develop highly-trained individuals by providing a unique, multidisciplinary experience for postdoctoral fellows. Dr. Chen is honored and privileged to be one of the three postdoctoral candidates to receive this prestigious grant in its inaugural year. He is excited to use the generous resources offered by the grant to investigate the cell of origin for brain tumors, specifically low-grade gliomas.

Kyra Rosen Joins the NF Center

The NF Center recently welcomed a new undergraduate student, Kyra Rosen, to the team. Kyra studies philosophy and art history at Washington University in St. Louis, and is pursuing a career in medicine and public health. In the NF Center, she will be researching access to healthcare services for those with NF.

International NF Collaborative Research Reveals Brain Sex Differences

As part of a Berlin Institute of Health Einstein Fellowship, investigators at the Max Delbrück Center in Berlin worked with NF Center Director, David H. Gutmann, to discover sex differences in microglia function.

In this study, researchers in the laboratory of Professor Helmut Kettenmann found that mouse brain cells, called microglia, react differently to Neurofibromatosis type 1 (NF1) gene mutations. Whereas female mouse microglia function similarly to normal microglia, male Nf1-mutant microglia have prominent defects in their ability to engulf foreign materials (phagocytosis), move in response to injury (motility), and conduct electrical impulses. Importantly, the team found that these defects result from a male-specific Nf1-mutant defect in cyclic AMP signaling.

This exciting work establishes that NF1 mutations can have different effects in males and females, and sets the stage for future studies that aim to determine how sex and genetic mutation intersect to govern clinical outcomes in people with NF1.

The study was recently published in Neurobiology of Disease.


Elmadany N, Logiacco F, Buonfiglioli A, Haage VC, Wright-Jin EC, Schattenberg A, Papawassiliou RM, Kettenmann H, Semtner M, Gutmann DH. Neurofibromatosis 1 – Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects. Neurobiol Dis. 2020 Oct;144:105030. doi: 10.1016/j.nbd.2020.105030. Epub 2020 Jul 29. PMID: 32736084 

Gutmann Receives Award from Neurological Association

Honored for work on role of immune system in brain tumors


David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor and Vice Chair for Research Affairs in the Department of Neurology at Washington University School of Medicine in St. Louis, has received the George W. Jacoby Award from the American Neurological Association for his discoveries on the role of the immune system in brain tumors.

The award is given once every three years to a scientist who has done especially noteworthy experimental work on any neurologic or psychiatric subject. Gutmann was recognized for a body of research showing that two kinds of immune cells – microglia and T cells – control the formation and growth of brain tumors in mice, similar to those arising in children with Neurofibromatosis type 1 (NF1). The findings could lead to new ways to help doctors predict which brain tumors are most likely to become life-threatening, and opens up new avenues to prevent or treat brain tumors.

Dr. Gutmann accepted the award at the American Neurological Association annual (virtual) meeting, in early October.

 

Original publication – Washington University School of Medicine, News Hub Website. Written by Tamara Bhandari, Senior Medical Science Writer.

Alexander Chen joins the Gutmann Laboratory

Alexander S. Chen, PhD recently joined the research laboratory of NF Center Director, David H. Gutmann, MD, PhD, as a postdoctoral research scientist. Dr. Chen completed his PhD training in Cancer Biology at Emory University in Atlanta, Georgia. Under the mentorship of Renee D. Read, PhD, Dr. Chen investigated how the novel protein kinases RIOK2 and Drak/STK17A are regulated by epidermal growth factor receptor signaling in malignant brain tumors.

As a postdoctoral research scientist, Dr. Chen will focus on the use of human induced pluripotent stem cells to model low-grade gliomas. More specifically, Dr. Chen will investigate how distinct driver mutations in progenitor cells are responsible for the unique spatial and temporal patterning of pediatric low-grade gliomas.

Gutmann Awarded Three-Year Drug Discovery Grant

 

David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor and Vice Chair for Research Affairs in the Department of Neurology at the Washington University School of Medicine, was awarded a three-year grant from the Pediatric Brain Tumor Foundation.

The Pediatric Brain Tumor Foundation award will support Dr. Gutmann’s research on pediatric low-grade astrocytomas (PLGAs), benign brain tumors. In the past, there have been few human PLGA models developed for drug and biomarker discovery research. By utilizing human induced pluripotent stem cell (hiPSC) engineering, the long-term goal of this project hopes to develop and characterize a series of human PLGA models that reflect the genetic diversity found in childhood brain tumors. Using hiPSCs engineered with pediatric brain tumor mutations, Dr. Gutmann and his team have generated early phase models of these cancers in mice.

The Pediatric Brain Tumor Foundation is a nonprofit organization that has provided more than 44 million dollars in grants for childhood brain tumor research.

NF1 Researchers Investigate the Role of MicroRNA in NF1-Associated Tumors

Dr. David H. Gutmann, and fellow researchers at John’s Hopkins University, confirmed the importance of microRNA in the biology of glioma tumors in NF1. MicroRNAs are small, noncoding molecules that control how cells build proteins. Previous findings have shown that the levels of different types of microRNA molecules help determine the way cells function. The levels of these microRNAs in cancer cells may be important in determining cancer severity. However, very little research has been done investigating the role of microRNAs in NF1.

In a recent study published in Neuropathology and Applied Neurobiology, the research team investigated the role of microRNAs in NF1-associated gliomas. They reported new findings regarding the levels of various microRNA molecules in both high grade and low-grade glioma tumors. These results imply that microRNA molecules may be useful biomarkers for screening and monitoring NF1 patients, and could be possible therapeutic targets for NF1-associated glioma tumors.


Nix JS, Yuan M, Imada EL, Ames H, Marchionni L, Gutmann DH, Rodriguez FJ. Global microRNA profiling identified miR-10b-5p as a regulator of neurofibromatosis 1 (NF1)-glioma migration. Neuropathol Appl Neurobiol. 2020 Jun 30. doi: 10.1111/nan.12641. Online ahead of print. PMID: 32603552

Dr. Xiaofan (Gary) Guo Successfully Defends PhD Thesis

On June 5th, 2020, Dr. Xiaofan (Gary) Guo successfully defended his PhD thesis entitled “Immune Regulation of Brain Tumors”. Dr. Guo was a visiting MD/Ph.D. student in the laboratory of Dr. David H. Gutmann from 2017-2020, where he sought to define the interactions between neurons, immune cells and tumor cells in NF1-associated optic pathway gliomas. Gary’s beautiful work on the “neuron-immune-cancer cell axis” was published last year in Neuro-Oncology, and earlier this year in Nature Communications. Dr. Guo is currently a Neurology resident at Loma Linda University.

New Targets for Childhood Brain Tumors Identified

Orginally published by the School of Medicine – The Record, on 5/1/2020 – Written by Tamara Bhandari.

Neurons, immune cells work together to promote tumor growth in neurofibromatosis type 1

People with the genetic condition neurofibromatosis type 1 (NF1) are prone to developing tumors on nervous system tissue. A new study from Washington University School of Medicine in St. Louis has found that the development and growth of such tumors are driven by nearby noncancerous neurons and immune cells. The findings point to potential new therapeutic targets for people with NF1. (Image: Getty Images)

Children with the genetic condition neurofibromatosis type 1 (NF1) can develop brain and nerve tumors. If a tumor develops within the optic nerve, which connects the eye and the brain, the child may lose his or her vision.

New research at Washington University School of Medicine in St. Louis indicates that the growth of these brain tumors is driven by nearby noncancerous neurons and immune cells, and that targeting immune cells slows tumor growth in mice. The findings, published May 1 in Nature Communications, point to new potential treatments for low-grade brain tumors in people with NF1.

“The fact that nerve cells and immune cells interact to support a tumor is a new way of thinking about how tumors develop and thrive,” said senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology and director of the Washington University Neurofibromatosis Center. “These tumors are arising in the nervous system, but until recently, few people had considered that the nerve cells themselves could be playing a role in tumor development and growth. These findings show that we have to consider nerve cells as participants, if not essential drivers, of cancer development.”

NF1 affects about one in every 3,000 people. It is caused by any one of a variety of mutations in the NF1 gene. While people with NF1 usually come to medical attention for birthmarks on their skin, nearly one in five children with NF1 will develop a brain tumor on the optic nerve, called an optic glioma.

To better understand what drives the development and growth of these brain tumors in people with NF1, first author Xiaofan Guo, MD, a graduate student in Gutmann’s research laboratory, and colleagues studied mice with NF1 mutations and optic gliomas. The team previously had discovered that the tumor cells in optic gliomas are interspersed with immune cells that help drive tumor formation and growth. But there is also another cell type in the vicinity of the tumor: neurons.

Suspecting that neurons also might be contributing to tumor growth, the researchers examined human neurons with NF1 mutations that had been grown from stem cells. They discovered that the neurons release a protein that activates immune cells known as T cells, which then produce proteins that promote the growth of tumor cells. The findings jibe with data from people with low-grade gliomas. By analyzing two publicly available datasets, the researchers found that patients whose tumors had more of a kind of T cell known as CD8+ T cells had reduced overall survival.

Disrupting the communication between neurons, T cells and tumor cells potentially could slow the growth of tumors, the researchers said. In the new study, they removed T cells from mice with optic gliomas, or prevented T cells from getting into the brains of such mice. In both scenarios, the researchers found that the optic gliomas grew more slowly in the absence of T cells.

“What we have here is a new way of thinking about how neurons and immune cells interact to control tumor growth, adding important new insights to the emerging field of cancer neuroscience,” Gutmann said. “We are excited about harnessing these critical interactions to develop new therapeutic strategies for childhood brain tumors.”


Guo X, Pan Y, Xiong M, Sanapala S, Anastasaki C, Cobb O, Dahiya S, Gutmann DH. Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth. Nature Communications. May 1, 2020. DOI: 10.1038/s41467-020-15770-3
This work was funded by the National Institute of Neurological Disorders and Stroke, grant number 1-R35-NS07211-01, the McDonnell Center for Cellular and Molecular Neuroscience; and the National Institutes of Health (NIH), grant number 1-R50-CA233164-01.