RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma
- 1Baylor College of Medicine
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.
Related
- The neuronal plasticity gene CRTC1 links survival with mitochondrial programs and tumor microenvironment features in Group 3 β medulloblastoma
- Targeting autocrine CCL2 signaling reveals oncogenic networks and prognostic biomarkers in medulloblastoma
- CCR2 is a potential biomarker and therapeutic target in Group 3 medulloblastoma
- Clustered structural variant hotspots enable oncogenic addiction and plasticity in osteosarcoma
- Oncogenic transformation proceeds through a transient state of cellular plasticity constrained by lineage-specific barriers
BibTeX
@misc{sah2026rbfox2,
title = {{RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma}},
author = {R. K. Sah and X. Yan and L. Louis and N. Gonzales and U. Tsogt and B. He and L. G. Hoefner and L. Lecomte and M. Bartels and C. A. Le Roux and A. C. Starner and I. Basili and O. Ayrault and E. L. Van Nostrand and O. Saulnier and J. Zagozewski and T. E. Werbowetski-Ogilvie},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.756284},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756284v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma
AU - R. K. Sah
AU - X. Yan
AU - L. Louis
AU - N. Gonzales
AU - U. Tsogt
AU - B. He
AU - L. G. Hoefner
AU - L. Lecomte
AU - M. Bartels
AU - C. A. Le Roux
AU - A. C. Starner
AU - I. Basili
AU - O. Ayrault
AU - E. L. Van Nostrand
AU - O. Saulnier
AU - J. Zagozewski
AU - T. E. Werbowetski-Ogilvie
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.756284
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.756284v1
AB - 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.
ER -