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

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Loss-of-function mutations in RBM10 are frequently observed in metastatic thyroid cancers.
• RBM10 plays a crucial role in regulating alternative splicing, particularly cassette exons.

Purpose of the Study:

• To investigate the functional consequences of RBM10 loss on transcriptome-wide splicing.
• To elucidate the molecular mechanisms by which RBM10 deficiency contributes to thyroid cancer metastasis.
• To identify potential therapeutic targets for RBM10-deficient thyroid cancers.

Main Methods:

• Transcriptome analysis (RNA-sequencing) of RBM10-null cells and RBM10-expressing cells.
• Functional assays measuring cell migration, velocity, and invasiveness.
• CRISPR-Cas9 screening to identify synthetic lethal interactions with RBM10 loss.

Main Results:

• RBM10 loss leads to aberrant splicing, favoring exon inclusion of genes involved in cell migration and RHO/RAC signaling.
• Increased cell velocity and invasiveness were observed in RBM10-deficient cells, linked to altered splicing of vinculin (VCL), tenascin C (TNC), and CD44.
• RBM10 loss activates RAC1 signaling and promotes metastasis in a mouse model, which can be reversed by RBM10 re-expression or targeting specific inclusion isoforms.
• CRISPR-Cas9 screening identified NFκB pathway components as essential for the viability of RBM10-null cells.

Conclusions:

• RBM10 loss drives thyroid cancer metastasis through altered splicing of extracellular matrix and cytoskeletal interaction genes, leading to RAC1 activation.
• Targeting NFκB effectors represents a promising therapeutic strategy for RBM10-mutated, metastatic thyroid cancers.