RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs

• Published in: The Journal of experimental medicine Vol. 222; no. 5
• Main Authors: Krishnamoorthy, Gnana P., Glover, Anthony R., Untch, Brian R., Sigcha-Coello, Nickole, Xu, Bin, Vukel, Dina, Liu, Yi, Tiedje, Vera, Pineda, Jose Mario Bello, Berman, Katherine, Tamarapu, Prasanna P., Acuña-Ruiz, Adrian, Saqcena, Mahesh, de Stanchina, Elisa, Boucai, Laura, Ghossein, Ronald A., Knauf, Jeffrey A., Abdel-Wahab, Omar, Bradley, Robert K., Fagin, James A.
• Format: Journal Article
• Language: English
• Published: United States 05.05.2025
• Subjects: Alternative Splicing; Animals; Cell Line, Tumor; Cell Movement - genetics; Cytoskeleton - genetics; Cytoskeleton - metabolism; Exons - genetics; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Mice; Neoplasm Metastasis - genetics; rac1 GTP-Binding Protein - metabolism; RNA Splicing - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Tenascin - genetics; Tenascin - metabolism; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Vinculin - genetics; Vinculin - metabolism
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20241029

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM–cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.