Behind the screen! The story of the coolest research I have ever done! It all started back in 2012 when I joined Dr Sean Lawler’s Translational Neurooncology group in Leeds. The Yorkshire Cancer Research funded project to carry out a high throughput, high content screen to create a resource for the scientific community and identify novel cytotoxic microRNAs in adult and paediatric glioblastoma was really exciting. The screen itself took a year to optimise, as you would imagine, carrying out such an experiment in stringent conditions to collect a robust dataset required a lot of time and effort. Around this time, Dr Lawler relocated his group to Harvard. I joined Prof. Susan Short’s group and with her support I then carried out the remainder for the research with Sean as advisor to continue guiding and shaping the project.
The first striking result of the screen was the 70% overlap between microRNAs with significant cytotoxicity in the adult and paediatric cell lines. Given the genetic and clinical differences in adult and paediatric glioblastomas, such a high level of concordance was highly unexpected and extremely interesting. Adding to our surprise, we found that one of our strongest candidates, microRNA-1300, it was very poorly studied and represented an exciting, novel microRNA to study.
The validation of microRNA-1300 took us on a fantastic journey! First, we discovered that it consistently caused cell cycle arrest in G2/M followed by apoptosis in all glioblastoma cell lines tested: adult, paediatric, established and patient-derived. Furthermore, we found that terminally differentiated patient-derived glioblastoma cells which divide very slowly were not affected by transfection with microRNA-1300, which represents a very promising window for therapeutic application in glioblastoma.
The cell cycle arrest data led us to go back to the images from the high-content screen and analyse them in more detail, which revealed the striking binucleated phenotype (see image above).
This was the first clue as to the previously undescribed, physiological role of microRNA-1300 as a key regulator of the megakaryocyte differentiation pathway and more particularly in endomitosis, which we went on to characterise.
Our final, pilot experiment in a preclinical mouse model of glioblastoma showed promising results for the use of a mimic of microRNA-1300 as a therapeutic agent.
There is still a lot to discover about the role and downstream mechanisms of microRNA-1300 in endomitosis. So far, we have only been able to validate one of its potential 21 target genes associated with cytokinesis. Further validation is warranted for the use of a microRNA-1300 mimic as a therapeutic agent: combination with current therapies, timing, delivery mechanism….
Starting by looking for novel, potent, cytotoxic microRNAs in glioblastoma to find such a candidate with a role in platelet formation allies both my background in haematology and my new expertise in glioblastoma. This truly has been an exciting, at times difficult (as research often is) but most rewarding journey and I am so glad to see it published in Oncogene. I hope you enjoy reading it and I look forward to the future developments which will no doubt stem from it!