MYCN Amplified Neuroblastoma Requires the mRNA Translation Regulator eEF2 Kinase to Adapt to Nutrient Deprivation
This week we profile a recent publication in Cell Death and Differentiation from the laboratory of Dr. Poul Sorensen (centre) at the BC Cancer Research Centre.
Can you provide an overview of your lab’s current research focus?
In our lab we are focused on novel approaches to target childhood cancers. A major theme is to study how different stresses of the tumour microenvironment affect childhood cancer cells, including oxidative stress, hypoxia, nutrient deprivation, and genotoxic stress. Each stress form is potentially lethal unless tumour cells can acutely adapt to it. However, stress adaptation can make cells hardier and can lead to the emergence of clones with aggressive phenotypes, including metastatic capacity. Adaptation has been widely attributed to genetic and epigenetic mechanisms. However, recent studies including our own suggests that acute stress adaptation occurs in large part through rapid changes in mRNA translation, which is the last step of protein synthesis. We postulate that adaptation of tumour cells to microenvironmental stress through altered mRNA translation and protein synthesis leads to cell clonal selection and metastasis. We have therefore been probing mechanisms by which childhood cancer cells activate stress responses as an adaptive response. We hope that by studying this process, we will be able to identify ways to inhibit these processes, in turn leading to new therapeutic targets in aggressive childhood cancers that might not otherwise be evident using genomic methodologies.
What is the significance of the findings in this publication?
Every day, 43 children are diagnosed with cancer in North America. Although there have been clear improvements in the treatment of many forms of childhood cancer, the outcome for patients with recurrent or metastatic disease remains dismal and almost unchanged for decades. Moreover, current therapies have very serious side effects on the developing child. This is particularly the case for aggressive childhood cancers such as neuroblastoma, where it is essential to discover targetable alterations typical of cancer cells but which spare normal cells. Our recent publication shows that a protein called eEF2K helps a highly aggressive and therapy resistant subtype of neuroblastoma to survive and proliferate even when it becomes severely limited in nutrients. These tumours have high expression levels of a gene called MYCN, and eEF2K appears to favour survival of high MYCN expressing tumour cells. Interestingly, neuroblastoma cells produce very high amounts of eEF2K, as opposed to normal organs. This means that blocking the action of eEF2K in patients affected by neuroblastoma might selectively kill tumour cells, but with no or only minor side effects on normal cells.
What are the next steps for this research?
A major next milestone is to combine eEF2K inhibition with widely available drugs that decrease blood glucose levels and deprive tumours of nutrients. The latter drugs are extremely safe and are currently used, for example, in the treatment of diabetes. We believe that by combining these two very different therapeutic approaches will lead to synthetic lethality of neuroblastoma cells while sparing normal tissues.
This work was supported by:
We are extremely grateful to the Canadian Cancer Society for providing support for the study, and to the British Columbia Cancer Foundation for funds donated through Team Finn and other generous riders in the Ride to Conquer Cancer.