RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs Journal Article
| Authors: | Krishnamoorthy, G. P.; Glover, A. R.; Untch, B. R.; Sigcha-Coello, N.; Xu, B.; Vukel, D.; Liu, Y.; Tiedje, V.; Pineda, J. M. B.; Berman, K.; Tamarapu, P. P.; Acuña-Ruiz, A.; Saqcena, M.; de Stanchina, E.; Boucai, L.; Ghossein, R. A.; Knauf, J. A.; Abdel-Wahab, O.; Bradley, R. K.; Fagin, J. A. |
| Article Title: | RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs |
| 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. |
| Keywords: | exon; genetics; exons; mouse; animal; metabolism; animals; mice; metastasis; cell motion; pathology; cell line, tumor; extracellular matrix; rna binding protein; gene expression regulation; rna-binding proteins; gene expression regulation, neoplastic; messenger rna; rna, messenger; tumor cell line; neoplasm metastasis; alternative splicing; alternative rna splicing; cell movement; thyroid neoplasms; protein p21; proto-oncogene proteins p21(ras); cytoskeleton; thyroid tumor; rna splicing; rac1 protein; rac1 gtp-binding protein; humans; human; hyaluronic acid binding protein; rbm10 protein, human; hyaluronan receptors; hras protein, mouse |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 222 |
| Issue: | 5 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2025-05-05 |
| Language: | English |
| DOI: | 10.1084/jem.20241029 |
| PUBMED: | 39992626 |
| PROVIDER: | scopus |
| PMCID: | PMC11849553 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is James Fagin -- Source: Scopus |
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