Medulloblastoma

Why do malignant tumors develop in the brains of young children during their developmental stages? Through collaboration with our team and leveraging our advanced imaging technology, a French research group has finally uncovered the pathogenic mechanism of malignant pediatric brain tumors this year. This breakthrough has been applied to the development of anti-cancer therapies. This study was recently published in the top-ranked international journal in developmental biology《Developmental Cell》.

Our team focused on medulloblastoma, the most common malignant brain tumor in children. This type accounts for approximately 14.5% of intracranial tumors in young children. These tumors often block the brain's ventricles, causing increased intracranial pressure or hydrocephalus. Without surgical removal, radiotherapy, or chemotherapy, metastasis is highly lethal.

This figure explains how overexpression of Atoh1 leads to the malignancy of cerebellar stem cells.

In the past, scientists have known that a transcription factor called Atoh1 is associated with medulloblastoma, a type of cerebellar tumor, but the mechanism of medulloblastoma. This question had perplexed scientists at the Curie Institute in France, as they were unsure how to study the connection in animal models. Five years ago, through Taiwan-France exchange programs, the French team began collaborating with our laboratory. Leveraging our expertise in neural stem cell research and utilizing the "cerebellar electroporation" technique, we successfully tracked the developmental process of cerebellar neural stem cells in mice for the first time. Under the microscope, we were able to observe the transformation of neural stem cells into cancerous cells, finally solving this long-standing mystery in the scientific community.

During the development of the cerebellum in infants, primitive "cerebellar neural stem cells" continuously divide and differentiate, enabling the formation of normal cerebellar cells. Our team observed a unique feature of these cerebellar neural stem cells: they possess a structure resembling an antenna, called the "primary cilium." This structure allows the cells to receive external signals and activate a series of molecular pathways that promote continuous division during development, producing cerebellar cells. Dr. Chia-Hsiang Chang, the first author, observed how the transcription factor Atoh1 influences the developmental process of cerebellar cells through a microscope. In addition, he unexpectedly discovered that overexpression of the Atoh1 transcription factor in brain tumor cells leads to hyperactivation of this "antenna," and subsequent excessive division of cerebellar neural stem cells, and eventually causes cancer.

Prof. Jin-Wu Tsai (left)、Dr. Hsin-Hung Chen (right) of Neurological Institute, Taipei Veterans General Hospital.

Dr. Hsin-Hung Chen from the Neurological Institute at Taipei Veterans General Hospital stated that the most common symptoms in children with brain tumors are headaches, nausea, and vomiting, which are often mistaken for a common cold. If cold-like symptoms persist or worsen beyond three days without improvement, it warrants caution. Other symptoms may include limb weakness, lack of coordination in activities like movement or handwriting, unsteady walking, and frequent falls. Current research indicates that while there hasn’t been a significant increase in childhood brain cancer in Taiwan, children under three years old should avoid radiation exposure and unnecessary radiological examinations or treatments. For medulloblastoma, the most critical prognostic factor remains surgery. Safely removing over 98% of the tumor, combined with postoperative radiotherapy and chemotherapy, leads to a high cure rate if detected and treated early. However, for patients with metastasis, the five-year survival rate drops significantly, making early diagnosis essential. Preventing metastasis would greatly improve outcomes.

Professor Jin-Wu Tsai remarked that Marie Curie’s pioneering research on radioactive elements led to her long-term radiation exposure and eventual cancer, prompting France to establish the Curie Institute with a focus on tumor research. Similarly, National Yang Ming Chiao Tung University excels in brain science research and technology. Combining their respective strengths enabled this significant scientific breakthrough. Now that the pathogenic mechanisms of cerebellar tumors have been uncovered, future efforts to block this pathway could potentially prevent the malignant transformation of cerebellar neural stem cells, paving the way for new therapeutic opportunities for cerebellar tumors.

Prof. Olivier Ayrault (middle left) and Prof. Tsai (middle right) (left)；Dr. Chia-Hsiang Chang and Prof. Tsai (right)

This paper was co-authored by Professor Jin-Wu Tsai from the Institute of Brain Science at National Yang Ming Chiao Tung University (NYCU) and researcher Olivier Ayrault from the Curie Institute in France, with contributions from Prof. Won-Jing Wang and Prof. Wei-Yi Chen from Institute of Biochemistry and Molecular Biology at NYCU. The first author, Dr. Chia-Hsiang Chang, is an alumnus of Yang Ming University’s School of Medicine and a master’s graduate from the Institute of Brain Science. This year, he earned a Ph.D. from the Taiwan International Graduate Program in Molecular Medicine, jointly organized by National Yang Ming Chiao Tung University and Academia Sinica, marking him as another outstanding medical researcher nurtured by “physician-scientist” program of NYCU.

This study received support from Taiwan’s Ministry of Science and Technology under the Taiwan-France Orchid Program, the Ministry of Education’s Higher Education Sprout Project, and the College of Medicine’s Ten-Year Development Plan, representing the fruitful collaboration between Taiwan and France. This achievement follows Professor Tsai’s publication in 《Nature Communications》, which introduced a novel gene screening method. The current study marks another significant research milestone published in a top-tier international journal.

Team members of Prof. Olivier Ayrault came to Taiwan and visit our lab