The team of Dr. Katherine Borden, principal investigator at the Institute for Research in Immunology and Cancer (IRIC) at the Université de Montréal and professor at the Department of Pathology and Cell Biology of the Faculty of Medicine, published a study in the scientific journal eLife, conducted in collaboration with Dr. Vincent Hascall and Dr. Ronald Midura, principal investigators at the Cleveland Clinic, Ohio, USA, as well as collaborators from the Segal Cancer Centre of the Montreal Jewish general Hospital. This study describes the discovery of how the eukaryotic translation initiation factor 4E, eIF4E, changes the surface of cancer cells by increasing the production of Hyaluronic acid-rich coats and protrusions in favor of invasion and metastasis.

Over the past two decades, mechanisms regulating cancer invasion and metastasis are becoming increasingly evident. It is now believed that the extracellular microenvironment plays important roles in tumour growth and metastasis. The glycosaminoglycan Hyaluronan (HA) forms a major functional and structural constituent of this microenvironment. HA is not a passive player, but even plays roles in signaling events crucial to maintaining the cancer niche.  HA can also coat tumour cells and plays roles in migration, invasion and metastases. Despite its well-documented role in cancer, little is known about how HA is regulated or how it becomes elevated in cancer. “For instance, HA levels do not always correlate with the RNA levels of the corresponding biosynthetic enzymes indicating it is not under direct transcriptional control” says Dr. Borden. We show instead that HA is subjected to intricate, coordinated post-transcriptional control through eIF4E. Here, we show that eIF4E stimulates the production of the enzymes involved in the synthesis of the UDP-Glucuronic Acid and UDP-N-Acetyl Glucosamine precursors, as well as the hyaluronic acid synthase (HAS) enzyme that forms HA from these precursors at the cell surface. Further, eIF4E stimulates the production of the major HA receptor CD44 and its mediators of downstream signaling e.g. Ezrin and MMP9. eIF4E drives production through simultaneously promoting the nuclear mRNA export of the transcripts encoding these enzymes and co-factors. In some cases, eIF4E also increases the translational efficiency of these mRNAs. Consistent with its effects on the HA biosynthetic machinery, eIF4E overexpression on its own is sufficient to drive production of HA. High-eIF4E cells are coated by HA and also have HA-containing protrusions radiating from the cell surface. Inhibition of eIF4E is sufficient to reduce HA to background levels. In summary, eIF4E drives a post-transcriptional programme, i.e. an RNA regulon, which elevates HA and increases the levels of its requisite co-factors. This activity is required for the oncogenic activity of eIF4E.

Our studies also provide first evidence that leukemic cells (but not on CD34+ cells from healthy volunteers) can be sugar-coated. Bone homing of these cells has been shown to rely on leukemic CD44-endothelial HA interaction to mediate the rolling of these cells on the endothelial wall. We propose that HA rich protrusions on the surface are required for the homing process post-extravasation. It is plausible that once inside the bone marrow, leukemic cells use their HA coats/protrusions to invade through the extracellular matrix towards the niche where they can hide and escape treatment.  Alternatively, the HA-CD44 interaction can also play a role in cell-cell communication between cancer cells or cancer cells with bone marrow cells in favor of survival or might mediate bone marrow exit of Acute Myeloid Leukemia (AML) cells (a topic which to date remains largely uncovered).

From the eIF4E perspective, these studies demonstrate for the first time that HA is required for eIF4E mediated invasion and migration. Further, it demonstrates that eIF4E can re-model the cell surface, in a way that mediates (at least in part) its oncogenic activity. The traditional view is that eIF4E increases invasion and metastasis through increasing levels of VEGF and various MMPs which are excreted. However, our studies provide a completely novel means through which eIF4E can modulate the surface architecture.

Our studies provide novel insights into how HA production and activity become dysregulated in cancer. “These architectural changes are not observable by light microscopy because the HA filaments are too narrow (120-130 nm), and thus have gone undetected for decades” says Dr. Zahreddine. We show that Hyaluronidase treatment can inhibit the oncogenic activities of eIF4E in vitro suggesting that this could have important implications for future drug design strategies. eIF4E has been targeted with ribavirin in high-eIF4E AML patients in early stage clinical studies with promising results. These studies suggest combinations of Hyaluronidase and ribavirin could be beneficial. “Indeed, we are in the process of designing a trial to test this idea in AML patients with our clinical collaborators” says Dr. Borden.