RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma
Sah, R. K.; Yan, X.; Louis, L.; Gonzales, N.; Tsogt, U.; He, B.; Hoefner, L. G.; Lecomte, L.; Bartels, M.; Le Roux, C. A.; Starner, A. C.; Basili, I.; Ayrault, O.; Van Nostrand, E. L.; Saulnier, O.; Zagozewski, J.; Werbowetski-Ogilvie, T. E.
Show abstract
Cancer cell plasticity underlies tumor progression, metastasis and therapeutic resistance, yet how RNA-binding proteins regulate malignant state transitions remains poorly defined. Here, we identify the splicing regulator RBFOX2 as a suppressor of oncogenic cell plasticity in Group 3 medulloblastoma (MB). OTX2 antagonizes RBFOX2 by directing an opposing alternative splicing program that mirrors developmental origins and controls cytoskeletal dynamics and cell state transitions. Mechanistically, OTX2 alters the RBFOX2 RNA-binding landscape, limiting RBFOX2 engagement at cytoskeletal loci and suppressing exon inclusion. RBFOX2 loss rewires splicing and transcriptional outputs to promote highly plastic proliferative, mesenchymal-like and undifferentiated cellular states associated with enhanced oncogenic properties. Consistent with these findings, RBFOX2low states mark highly plastic cell populations in patient tumors and xenografts, positioning RBFOX2 as a determinant of malignant cell stability. Together, these findings establish RBFOX2 as a developmental gatekeeper that restrains malignant cell plasticity through coordinated control of cytoskeletal gene programs.
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