Scientists from St. Jude Children's Research Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Uppsala University have identified a molecular program shared by several types of brain tumors. Their research focused on pineoblastoma, a rare pediatric brain tumor, and involved assembling the largest group of such tumors studied at single-cell resolution.
Paul Northcott, PhD, director of the Center of Excellence in Neuro-Oncology Sciences at St. Jude and co-senior author of the study, said: "Pineoblastoma is extremely rare; St. Jude treats only a handful of cases each year. By collaborating with other institutions, we went much deeper than previous profiling efforts to understand where these tumors come from, how they overlap or differ at single-cell resolution, and what makes them vulnerable."
The team created the first single-cell atlas mapping normal pineal gland development to compare with gene expression data from 38 pineoblastoma patients. They discovered that early cells known as pinealocyte progenitors closely resemble these tumors. Mouse models were developed by altering five different genes linked to pineoblastoma in these progenitor cells; all models matched human subtypes both molecularly and histologically.
Despite differences among cancer drivers in various subtypes, all showed high expression levels of genes related to light sensitivity—genes normally active in the pineal gland for circadian rhythm regulation. Northcott explained: "We saw a recurring theme that was related to light sensitivity. The pineal gland plays an important role in circadian rhythm and interpreting light from the retina, so it normally expresses a set of photoreceptor and phototransduction genes. Not only are these same genes expressed in pineoblastoma, but they are expressed at very high levels, suggesting the tumors might be 'addicted' to them."
He added: "The light-sensing signature reminded us of a very similar program that we had seen in a subtype of another brain cancer, Group 3 medulloblastoma. When we looked closer at other cancers, we saw the same genes, transcription factors and biomarkers of this program were shared between anatomically distinct central nervous system tumor types, including tumors of the pineal gland, retina and cerebellum."
Using CRISPR technology to remove these key genes from cell lines derived from pineoblastoma, medulloblastoma and retinoblastoma led to cell death across all three cancer types. This suggests that their survival depends on this common gene signature.
Northcott stated: "We found a subset of these light-sensing genes to be very strong selective dependencies in these particular cancer types. With that information, we've opened the door to explore therapeutically targeting this shared signature across multiple brain tumor types in the future."
The research was published in Cancer Cell and included contributions from scientists at several institutions worldwide.
The project received support through grants from organizations such as The Mark Foundation for Cancer Research (Emerging Leader Award), St. Baldrick's Foundation (Robert J. Arceci Innovation Award), National Cancer Institute (1R01CA259372-01A1 and 1R01CA270785-01A1), Andruzzi Foundation, Alex's Lemonade Stand Foundation (A-Award), John W. and Pamela A. Cuming Fund, Solving Kids' Cancer/The Bibi Fund, Burroughs Wellcome Fund (Career Award for Medical Scientist), Sontag Foundation (Distinguished Scientist Award), Erwin Schrödinger Fellowship/Austrian Science Fund (J-4311), Swedish Research Council, Swedish Cancer Society/Childhood Cancer Fund/Brain Fund as well as training grants like Li Shu Pui Medical Foundation Training Grant and Lin Kin Pang-HKU Foundation Scholarship.
