A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing

• Published in: Nature cell biology Vol. 26; no. 8; pp. 1233 - 1246
• Main Authors: Saulnier, Olivier, Zagozewski, Jamie, Liang, Lisa, Hendrikse, Liam D., Layug, Paul, Gordon, Victor, Aldinger, Kimberly A., Haldipur, Parthiv, Borlase, Stephanie, Coudière-Morrison, Ludivine, Cai, Ting, Martell, Emma, Gonzales, Naomi M., Palidwor, Gareth, Porter, Christopher J., Richard, Stéphane, Sharif, Tanveer, Millen, Kathleen J., Doble, Brad W., Taylor, Michael D., Werbowetski-Ogilvie, Tamra E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2024; Nature Publishing Group
• Subjects: 13; 13/100; 13/95; 38; 38/91; 59; 59/57; 631/136/142; 631/67/1922; 631/67/71; 82; 82/58; Alternative splicing; Alternative Splicing - genetics; Animals; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell fate; Cell Line, Tumor; Cell Proliferation; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Cerebellum; Developmental Biology; Gene Expression Regulation, Neoplastic; Humans; In vivo methods and tests; Life Sciences; Medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Otx Transcription Factors - genetics; Otx Transcription Factors - metabolism; Otx2 protein; Protein interaction; Proteins; Stem Cells; Tumors
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-024-01460-5

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression. Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.