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.

doi:10.64898/2026.10.02.756284

bioRxiv · 10.64898/2026.10.02.756284

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.

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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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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.. 2026-10-06. RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma. https://doi.org/10.64898/2026.10.02.756284

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