Katherine Borden, PhD
Professor, Pharmacology
Research Program
Cancer-Focused Research
Our lab's work focuses on understanding the mechanisms and impact of dysregulated RNA metabolism in cancer focusing on Acute Myeloid Leukemia. RNA metabolism can be hijacked by cancer cells to re-write and/or amplify the message sent from the DNA. This in turn can underpin the oncogenic phenotype. We unearthed novel modes by which cancer cells hijack genetic information, in the form of messenger RNA, and demonstrated new mechanisms by which RNA maturation and RNA export influence cell physiology and support cancer growth. These findings drove first-in-class clinical trials demonstrating that targeting eIF4E and relevant RNA processing events represents a highly promising avenue for the development of novel therapeutics. These studies also revealed novel modes of drug resistance in patients that are targetable in patients. We use the eukaryotic translation initiation factor eIF4E as an exemplar. The eukaryotic translation initiation factor eIF4E is an m7G cap-binding protein which can escort messages through various RNA metabolism steps including translation. It is elevated in a wide array of cancers and is generally linked with poor prognosis. We focus in the lab on acute myeloid leukemia. Indeed, it has been known since the 1990s that eIF4E is present in both the nucleus and cytoplasm of eukaryotic cells. In the nucleus, eIF4E binds ~3000 transcripts and influences multiple stages of their processing. Our lab discovered that eIF4E could act in many facets of both nuclear and cytoplasmic RNA metabolism including regulating covalent modifications to the RNA such as capping and splicing, as well modify the export of many RNAs to the cytoplasm which of course segues into its cytoplasmic role in translating RNAs into proteins. A major research focus is to understand what sensitized RNAs to a certain level of regulation since the cap-alone does not imbue selectivity. Indeed, we identified cis-acting elements in RNAs (USER codes) that sensitize RNAs to export but not translation, as an example. A major research focus is to dissect eIF4E's physical interaction with the different RNA processing machinery and dissect the biochemical mechanisms related to how eIF4E can act in processes such as splicing, capping, export, how these RNAs are selected, and is this activity related to the oncogenic potential of eIF4E. We have also identified an interesting link between mitochondrial translation and eIF4E's nuclear activities which could be important for understanding how eIF4E can rescue cells from apoptotic stimuli. These are all active areas in the lab. eIF4E-targeted mRNAs can act in the same biochemical pathways whereby eIF4E coordinates biochemical responses as seen in RNA regulons. Indeed, we found that eIF4E can drive AML cell motility including invasion through human bone marrow cells and linked this to its impacts on RNA processing. We discovered that these pathways include the extracellular hyaluronan-CD44-ezrin signalling pathways- which are key for cell motility. Identification of these eIF4E-targets led to the finding that eIF4E enhances cell motility in cancer cells which is consistent with its frequent association with metastatic disease. We found that eIF4E through its RNA export activity elevates ezrin levels, and also directly binds to ezrin. These interactions become enriched at protrusions in actively invading AML cells. We found these protrusions are enriched in active translation. We are actively investigating what RNAs are translated here, if they provision actively migrating cells and similar. We also have evidence suggesting that ezrin may plan an unexpected and direct role in localized translation. This is being actively investigated. In our previous studies, we were the first to develop a means to target eIF4E in patients. We found that clinical targeting of eIF4E in high-eIF4E AML patients leads to objective clinical responses including complete remissions corresponding to eIF4E targeting in these patients in three published clinical trials. We are thus interested in identifying combination therapies for ribavirin (our eIF4E inhibitor) and AML. This is an ongoing area.