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Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A′ (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.

In this study we performed a systematic search to identify breast cancer-specific small non-coding RNAs, which we have collectively termed orphan non-coding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3’ end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its pro-metastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the pro-metastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also play a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies.