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Tracing the Origins of Aggressive Medulloblastoma

Aug 21, 2023, 16:31 PM by Nyla Sauter

Data from a new fetal brain atlas has helped a scientific team discover a collection of progenitor cells that give rise to aggressive "Group 3" medulloblastomas. Findings include identification of two genes that may serve as therapeutic targets. Mice with these tumors lived longer when bred to express reduced levels of these genes. 

Medulloblastoma (MB) is the most common malignant childhood brain tumor, with one type — Group 3 — being the most deadly. 

Until now, very little was known about the origins of Group 3 MB. University of Cincinnati Cancer Center researchers along with colleagues from three other countries were able to identify a specific type of progenitor cell responsible for tumor formation. The findings were published in November 2022 in Nature

“We identified a progenitor cell population in the early developing cerebellum,” says Qing Richard Lu, PhD, basic science researcher at the Cancer Center and scientific director of the Brain Tumor Center at Cincinnati Children’s. “These progenitor cells are highly abundant in aggressive medulloblastomas with excessive MYC gene copies, which drive tumor formation. This progenitor population may serve as a potential cell of origin for the aggressive medulloblastomas.” 

Even more promising, the researchers also identified two specific marker genes that activate the MYC oncogene to drive tumor cell growth: SOX11 and HNRNPH1. 

“These markers can be used in the clinic for disease prognosis,” Lu explains. Once they identified these biomarkers, the team used mouse models to discover if they were targetable. “We found that targeting those two genes can inhibit the growth of medulloblastoma tumor cells with excess MYC gene copies that we interpret as being the progeny of the progenitors.” 

This discovery was made after the multinational team of scientists led by Lu and other experts at Cincinnati Children’s developed an “atlas” of human brain development so detailed that it tracks growth steps down to changes at the single-cell level. 

“This study took the effort of 40 experts for nearly three years to complete,” Lu says. “It was worth so much effort because this new map guided us to a potential target for therapeutic intervention of aggressive medulloblastomas.” 

In addition to Lu, 15 other researchers at Cincinnati Children’s and University of Cincinnati co-authored the study, including Zaili Luo, PhD, a researcher in Dr. Lu's lab and first author on the Nature publication. International collaboration came from researchers at the Children’s Hospital of Fudan University, Xinhua Hospital, the Shanghai Jiao Tong University School of Medicine and Westlake University in China; the University of Cambridge in the UK; the University of Toronto in Canada; and Northwestern University in Evanston, Ill. 

Left: UMAP visualization of neural cell types from the developing human cerebella. Right: Predicted trajectories of neural cell-type fate transitions.

While this study focuses on medulloblastoma, the new atlas will help accelerate understanding of other conditions that result from disruptions in healthy early brain development, such as autism, attention-deficit hyperactivity disorder (ADHD), developmental dyslexia and pediatric cerebellar damage." ~ Qing Richard Lu, PhD