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.
RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs
Disclosures: A.R. Glover reported grants from RACS Foundation for Surgery Tour de Cure Cancer Research Scholarship and grants from NHMRC Neil Hamilton Fairley Early Career Fellowship (RG183080) during the conduct of the study. R.A. Ghossein reported grants from National Institute of Health during the conduct of the study. J.A. Knauf reported a patent to Treatment of HRAS-Driven Tumors licensed “Kura Oncology” and a patent to Targeting the adaptive responses of BRAF or RAS-mutant thyroid cancers to RAF/MEK inhibitors with bispecific antibodies to TSHR and/or HER pending. O. Abdel-Wahab reported grants from LOXO Oncology, Nurix Therapeutics, Codify Therapeutics, Minovia Therapeutics, and AstraZeneca during the conduct of the study. R.K. Bradley reported grants from Codify Therapeutics, personal fees from Codify Therapeutics, ″other″ from Synthesize Bio, and ″other″ from Codify Therapeutics outside the submitted work. R.K. Bradley is a founder and scientific advisor of Codify Therapeutics and Synthesize Bio and holds equity in both companies. R.K. Bradley has received research funding from Codify Therapeutics unrelated to the current work. J.A. Fagin reported a patent to Treatment of HRAS-Driven Tumors #WO/2015/164862 with royalties paid “Kura Oncology.” No other disclosures were reported.
