Researchers have uncovered a new way in which the protein OTX2 contributes to the advancement of medulloblastoma, a common and aggressive brain cancer in children. The study indicates that targeting OTX2 or its effects could be beneficial for therapeutic purposes.
In a recent report published in Nature Cell Biology, a team of researchers from Baylor College of Medicine, Texas Children’s Hospital, the University of Manitoba, and other collaborating institutions unveiled a novel mechanism through which the protein OTX2 fuels the progression of medulloblastoma, a prevalent aggressive brain cancer in children. The research suggests that focusing on OTX2 or its functions may hold promise for future therapeutic interventions.
“We view medulloblastoma stem cells as the initial source of the disease. These tumors originate from these cells early in the development of the cerebellum, the posterior region of the brain,” explained Dr. Tamra Werbowetski-Ogilvie, a co-corresponding author of the study and a professor specializing in pediatrics, hematology-oncology at Baylor, Texas Children’s Hospital, and an adjunct professor at the University of Manitoba. She added, “We already knew that OTX2 acts as a transcription factor in these stem cells – aiding them in transcribing genetic instructions into functional proteins. In this study, we delved into the additional roles of OTX2 in driving medulloblastoma development.”
The researchers carried out an extensive analysis of the proteins interacting with OTX2 in the cellular environment. “While we validated the known players, proteins involved in transcription, we also made a surprising finding that OTX2 interacts with a different set of proteins known as splicing factors,” the team shared.
Splicing factors play a crucial role in alternative splicing, a cellular process enabling cells to generate various proteins from the instructions encoded in a single gene. Dr. Werbowetski-Ogilvie used a kitchen analogy to explain, “Think of it as three chefs gathering to bake a cake. Each chef follows the same recipe but adds their unique touch. One uses extra chocolate, another swaps yogurt for butter, and the third includes shredded carrots. As a result, different versions of the cake emerge from the same recipe, with some tasting better than others.”
Similarly, alternative splicing allows a cell to combine gene components in diverse ways, resulting in the creation of different proteins. Some protein variants may promote normal stem cell growth, while others may not function correctly, potentially leading the cells towards disease.
“We discovered that OTX2 acts like the chef creating a less than desirable cake,” stated Dr. Werbowetski-Ogilvie. “OTX2 plays multiple roles in regulating the alternative splicing of genes that drive medulloblastoma development. For example, a specific variant of the PPHLN1 gene facilitates the growth and survival of medulloblastoma stem cells instead of normal development. This study is the first to demonstrate the functional role of alternative splicing in the progression of the most severe form of medulloblastoma.”
Significantly, the researchers found that disrupting the splicing of the PPHLN1 gene, using a morpholino drug targeting PPHLN1, resulted in reduced tumor growth, suggesting potential avenues for enhancing treatment strategies.
“This study underscores the effectiveness of comprehensive multi-tiered investigations, combined with collaborative efforts among teams with diverse expertise, in advancing our understanding of how OTX2 propels medulloblastoma,” emphasized Dr. Brad Doble, a co-senior author of the study and an associate professor holding the Bihler Chair in Stem Cell Research at the University of Manitoba’s Departments of Pediatrics, Child Health, Biochemistry, and Medical Genetics.
The implications of these findings extend beyond cancer research. Dr. Michael D. Taylor, a co-corresponding author and professor specializing in pediatrics, hematology-oncology, and neurosurgery at Baylor, Texas Children’s Hospital, and the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at Texas Children’s Cancer and Hematology Center, remarked, “It’s intriguing that a transcription factor is involved in regulating splicing, and that this splicing variation is critical not only in childhood brain cancer but also in the normal development of the human fetal hindbrain.”
Contributors to this study, among others, include Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M. Gonzales, Gareth Palidwor, Christopher J Porter, Stephane Richard, Tanveer Sharif, Kathleen J. Millen, and Brad W Doble.
Affiliated with various institutions such as Baylor College of Medicine, Texas Children’s Hospital, University of Manitoba, the Hospital for Sick Children in Toronto, Seattle Children’s Research Institute, and others, the authors collectively contribute to broadening the understanding of OTX2’s role in medulloblastoma.
