The oncogene eIF4E coordinates extracellular signalling in AML
Katherine Borden
PhDIRIC - Institute for Research in Immunology and Cancer
Project Term: July 1, 2019 - June 30, 2021
The oncoprotein eIF4E is dysregulated in many cancers including AML. We show that eIF4E drives production of the glycosaminoglycan hyaluronan (HA). Further, HA elevation alters the surface architecture of high-eIF4E AML cells and this is required for eIF4E’s oncogenic activity. We will explore HA’s involvement in AML and the efficacy of depleting HA in patients using hyaluronidase in a Phase I trial in AML.
Relative to normal cells, cancer cells are often characterized by substantial changes to their surface in order to mediate their oncogenic properties. Factors on these surfaces can include multidrug resistance transporters which pump drugs out of the cell, enzymes that are involved in breaking down the surrounding tissue to enable cancer cells to migrate and invade other parts of the body as well as features that help the cells survive in the tumour microenviroment. In this way, changes to the cell surface architecture can lead to dramatic alterations in how cells respond to growth signals, drugs and affect their mobility. We identified the oncoprotein eIF4E as a factor that could substantially alter the cell surface and identified this ability as critical for its cancer causing properties. eIF4E alters the surface by increasing the levels of a large sugar molecular known as hyaluronic acid (HA) and also of key factors that bind HA such as CD44. In fact, upon elevation of eIF4E, the cells become coated in HA and further, the HA forms protrusions radiating outward from the cell surface. If the HA is removed using a clinically available enzyme called hyaluronidase, the cells lose their cancer-causing properties in the lab even though they still have elevated eIF4E. This suggests that the HA is important for the activity of eIF4E. eIF4E is elevated in acute myeloid leukemia (AML), lymphomas and other hematological malignancies. In this renewal, we will further examine the functional effects of these HA mediated alterations to the cell surface and investigate the use of hyaluronidase in patients in AML in a Phase I trial as a first step in determining the safety and preliminary clinical utility of this approach.