Shared origins illuminate potential dependency across brain tumor types

Scientists studying the cellular origins of pineoblastoma discovered a dependency applicable to anatomically distinct brain tumor types, which may be therapeutically targetable.

MEMPHIS, Tenn., March 5, 2026 /PRNewswire/ -- Research uncovering the origin of pineoblastoma, a rare pediatric brain tumor, has also revealed a dependency across multiple brain tumor types that share a similar molecular program. Scientists at St. Jude Children's Research Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Uppsala University assembled and profiled the largest cohort of pineoblastoma tumors to date with single-cell resolution. They found a set of light-sensing-related genes essential to pineoblastoma formation in the developing pineal gland. They then extended the finding to medulloblastoma and retinoblastoma, indicating a common developmental state and a potential shared therapeutic dependency that could be targeted to improve their treatment. The findings were published today in Cancer Cell.

"Pineoblastoma is extremely rare; St. Jude treats only a handful of cases each year," said corresponding and co-senior author Paul Northcott, PhD, St. Jude Center of Excellence in Neuro-Oncology Sciences (CENOS) director, Cancer Center Neurobiology and Brain Tumor Program co-leader and Department of Developmental Neurobiology member. "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."

Illuminating a tumor origin

During early human development, brain cells rapidly expand, divide and migrate to form complex structures, such as the pineal gland. The pineal gland is a pinecone-shaped structure in the center of the brain that releases hormones, such as melatonin. The scientists believed that pineoblastomas arise when something goes wrong during the rapid development of the pineal gland. However, before they could investigate how things could go wrong, they first had to understand how things go right during normal development. To do so, they created the first single-cell atlas of normal pineal gland development, including all the cell types involved.

Once the researchers created their atlas, they measured gene expression in the cohort of rare tumor samples from 38 patients and compared it to normal pineal gland development. By measuring gene expression using single-cell RNA-sequencing, they found that a population of early cells called pinealocyte progenitors is the most similar to these tumors, implicating their role in pineoblastoma development. They created unique mouse models through the perturbation of five different pineoblastoma driver genes in these progenitors. The five models all faithfully resembled corresponding human subtypes based on extensive molecular and histological analysis.

Despite the subtypes having different cancer drivers, they all shared one notable gene expression signature. "We saw a recurring theme that was related to light sensitivity," Northcott said. "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."

Bringing a shared dependency into the light

"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," Northcott said. "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."

This abnormally expressed light-sensing signature indicated that this set of genes may be essential for these cancers to form and survive, suggesting a potential cross-tumor vulnerability. The scientists used CRISPR to remove genes from this signature in pineoblastoma, medulloblastoma and retinoblastoma cells, to see if it affected their growth. They found all three cancers had a shared dependence on those genes, as tumors died without them.

"We found a subset of these light-sensing genes to be very strong selective dependencies in these particular cancer types," Northcott said. "With that information, we've opened the door to explore therapeutically targeting this shared signature across multiple brain tumor types in the future."

Authors and funding

The study's co-first authors are Brian Gudenas, Anthony Liu and Shiekh Tanveer Ahmad, of St. Jude; Bernhard Englinger, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Miao Zhao, Uppsala University. The study's other co-senior authors are Fredrik Swartling, Uppsala University and Mariella Filbin, Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

The study's other authors are Leena Paul, Jennifer Hadley, Yiran Li, Melissa Batts, Priya Mittal, Stephanie Wu, Sara Lewis, Katie Han, Taha Soliman, Hong Lin, Laure Janke, Paul Klimo, Jr., Frederick Boop, Amar Gajjar, Giles Robinson and Brent Orr, St. Jude; Gabriela Rosén, Uppsala University; David Meredith, Harvard Medical School; Elke Pfaff and David Jones, Hopp Children's Cancer Center Heidelberg (KiTZ); Johannes Gojo, Medical University Vienna; Jennifer Cotter, University of Southern California and Sanda Alexandrescu, Boston Children's Hospital.

The study was supported by grants from The Mark Foundation (Emerging Leader Award), St. Baldrick's Foundation (Robert J. Arceci Innovation Award), the National Cancer Institute (1R01CA259372-01A1 and 1R01CA270785-01A1) the Andruzzi Foundation, Alex's Lemonade Stand Foundation (A-Award), John W. and Pamela A. Cuming, Solving Kids' Cancer, Inc./The Bibi Fund, the Burroughs Wellcome Fund (Career Award for Medical Scientist), the Sontag Foundation (Distinguished Scientist Award), the Erwin Schrödinger Fellowship of the Austrian Science Fund (J-4311), the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the Swedish Brain Fund, the Swedish Childhood Cancer Fund, the Li Shu Pui Medical Foundation Training Grant, the Lin Kin Pang-HKU Foundation Scholarship and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped increase overall childhood cancer survival rates from 20% to 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.

SOURCE St. Jude Children's Research Hospital