1. RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.
- Author
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Krishnamoorthy GP, Glover AR, Untch BR, Sigcha-Coello N, Xu B, Vukel D, Liu Y, Tiedje V, Pineda JMB, Berman K, Tamarapu PP, Acuña-Ruiz A, Saqcena M, de Stanchina E, Boucai L, Ghossein RA, Knauf JA, Abdel-Wahab O, Bradley RK, and Fagin JA
- Subjects
- Animals, Humans, Mice, Cytoskeleton metabolism, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Thyroid Neoplasms metabolism, Cell Line, Tumor, RNA Splicing genetics, Exons genetics, Alternative Splicing genetics, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Cell Movement genetics, Extracellular Matrix metabolism, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, rac1 GTP-Binding Protein metabolism, rac1 GTP-Binding Protein genetics, Neoplasm Metastasis, Hyaluronan Receptors metabolism, Hyaluronan Receptors genetics, RNA, Messenger genetics, RNA, Messenger metabolism
- Abstract
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., (© 2025 Krishnamoorthy et al.)
- Published
- 2025
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