Re-wiring of transcription and RNA processing is a hallmark of cancer, and thus the mechanisms that control gene expression have been studied for decades. However, it is now clear most protein-coding genes are regulated by mechanisms that both defy accepted dogmas and are altered in cancer. We have a long-standing track record of discovering these new mechanisms of RNA processing that regulate global gene expression in normal and disease states. For example, it has long been assumed that protein-coding genes yield linear mRNAs, but we and others have shown that many genes generate abundant noncoding circular RNAs.

Thousands of circular RNAs are dysregulated across cancers, yet it remains unk...

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Re-wiring of transcription and RNA processing is a hallmark of cancer, and thus the mechanisms that control gene expression have been studied for decades. However, it is now clear most protein-coding genes are regulated by mechanisms that both defy accepted dogmas and are altered in cancer. We have a long-standing track record of discovering these new mechanisms of RNA processing that regulate global gene expression in normal and disease states. For example, it has long been assumed that protein-coding genes yield linear mRNAs, but we and others have shown that many genes generate abundant noncoding circular RNAs.

Thousands of circular RNAs are dysregulated across cancers, yet it remains unknown how they impact cancer gene expression or therapeutic vulnerabilities. Likewise, it has been assumed that initiation of transcription governs regulation of RNA synthesis, but we showed that premature termination events are coordinated and catalyzed by the Integrator complex across the genome. Integrator is commonly mutated in cancer and is a potent dependency in some cancer types, but how Integrator dysfunction and aberrant transcription termination states contribute to cancer pathogenesis or response to therapy remains largely unknown.

At the Therapeutic Innovation Center at BCM, my lab will address these key gaps in knowledge by focusing on three primary goals:

1. Characterize and exploit aberrant circular RNA expression programs in breast cancer.
2. Develop a flexible circular RNA platform for pre-clinical tools and cancer therapeutics.
3. Define how aberrant transcription termination catalyzed by Integrator drives cancer.

These innovative studies will reveal novel paradigms for understanding the (de)regulation of gene expression in cancer as well as for precision cancer diagnosis/treatment. In addition, we will provide a critical framework that can be used to identify and target non-canonical RNAs that constitute previously unappreciated cancer dependencies.

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