In a report published in Nature Cell Biology, researchers at Baylor College of Medicine, Texas Children’s Hospital, the University of Manitoba, and collaborating institutions revealed an unexpected way in which the protein OTX2 drives the progression of medulloblastoma—the most common aggressive childhood brain cancer. The findings suggest that targeting OTX2 or its effects can have therapeutic relevance.
“We see medulloblastoma stem cells as the root of the disease. The tumors develop from these cells early during development of the cerebellum, the brain region located at the back of the head,” said co-corresponding author Dr. Tamra Werbowetski-Ogilvie, professor of pediatrics, hematology-oncology at Baylor, Texas Children’s and adjunct professor at the University of Manitoba. “We already knew that OTX2 is a transcription factor in these stem cells—it helps the cells transcribe the instructions in the genes into functional proteins. Here, we investigated what other roles OTX2 could play to generate medulloblastoma.”
The researchers conducted a comprehensive screening of the proteins that interact with OTX2 in the cell. “We confirmed the usual suspects, proteins involved in transcription, but unexpectedly, we discovered that OTX2 also interacts with other proteins called splicing factors.”
Splicing factors are involved in alternative splicing, a cellular process that allows cells to produce different proteins from the instructions encoded in a single gene. “Imagine that three cooks meet in the kitchen to bake a cake,” Werbowetski-Ogilvie said. “They all begin with the same instructions, but each cook adds a different twist to the cake. One cook uses more chocolate than the others; another cook substitutes yogurt for butter; and the third one adds shredded carrots to the cake. In the end, different versions of the cake emerge from the same recipe, and some may taste better than others.”
Alternative splicing is similar. A cell can combine different components of a transcribed gene (the ingredients in this analogy) in various ways, giving rise to different proteins. Some versions will promote normal stem cell development; others might not work; and some might lead to disease.
“We found that OTX2 is like a cook who makes an unpalatable cake,” Werbowetski-Ogilvie said. “OTX2 plays several roles in controlling alternative splicing of genes that fuel medulloblastoma development. For example, a specific version of the gene PPHLN1 promotes medulloblastoma stem cell growth and survival instead of normal growth. This is the first time that alternative splicing has been shown to play a functional role in developing this aggressive kind of medulloblastoma.”
Importantly, researchers discovered that disturbing PPHLN1 gene splicing with an anti-PPHLN1 drug called morpholino reduces tumor growth, opening new possibilities for improved treatments.
“This research demonstrates how unbiased multi-level studies combined with collaboration between teams with diverse skills advance our knowledge of how OTX2 drives medulloblastoma,” said co-senior author Dr. Brad Doble, associate professor and Bihler Chair in Stem Cell Research at University of Manitoba.
The findings have implications beyond cancer. “It is fascinating that a transcription factor would be moonlighting to control splicing and that this differential splicing should be important both in childhood brain cancer and normal development of human fetal hindbrain,” said co-corresponding author Dr. Michael D. Taylor, professor at Baylor and Texas Children’s Hospital.
Other contributors include Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger among others affiliated with Baylor College of Medicine; Texas Children's Hospital; University of Manitoba; Hospital for Sick Children – Toronto; Seattle Children’s Research Institute; PLS University – Paris; Institute Curie – Paris; University of Toronto; Brotman Baty Institute for Precision Medicine – Seattle; McGill University – Montreal; Ottawa Hospital Research Institute.
For financial support details for this project refer to their publication.
