Adam Kosti published a first author paper in Molecular Cancer Research in the January issue. His paper is entitled “ELF4 Is a Target of miR-124 and Promotes Neuroblastoma Proliferation and Undifferentiated State.”

What year are you? What program?

I am a fifth year Ph.D. candidate in the Integrated Biomedical Sciences program with a focus on Cancer Biology.

What are you studying in the lab?

I am in Dr. Luiz Penalva’s laboratory. His laboratory focuses on the role of post-transcriptional regulators (microRNAs and RNA-binding proteins) in neuronal cancers. My thesis research is focused on a group of tumor suppressor microRNAs and the oncogenic transcription factors that they regulate in glioblastoma multiforme.

Why is this important for the general public to know about?

DNA mutations that drive glioblastoma multiforme (malignant grade IV brain tumors) have been identified and well-studied. Despite characterization of these driver mutations, we still cannot capture all the aspects of glioma development. More importantly, therapies that target these mutations have not been as successful as hoped. We believe that focusing on genes that control glioma cell identity, specifically microRNAs and the genes that they regulate, we can identify new targets for therapy. In addition, microRNAs themselves can be used therapeutically. Although RNA therapeutics is still a very young field, examples of successful RNA-therapies already exist, and part of my thesis is testing microRNAs in preclinical animal models.

Tell me about your first author paper. What did you discover? Why was this interesting to you and your lab?

Two years before even starting the doctoral program, I had begun work on this paper without even knowing it. Working as a research assistant under Dr. Alexander Pertsemlidis, I helped characterize tumor suppressor microRNAs in neuroblastoma, a pediatric extracranial solid tumor. However, upon entering graduate school, I joined Dr. Penalva’s lab, where my project was focused on a network of transcriptional and post-transcriptional regulators (a microRNA-Transcription factor network) in glioblastoma, an adult cranial tumor. While glioblastoma and neuroblastoma differ in many regards, such as cell of origin, age, and location; they also had many things in common. Namely they are both neuronal in origin, arising from neural precursors that fail to differentiate (Glioblastoma from neural stem cells in the brain, while Neuroblastoma from migrating neural crest cells in the periphery). Due to their similarities, Dr. Penalva and Dr. Pertsemlidis decided to test whether this miRNA-transcription factor network regulated neuroblastoma cell fate. As a result, I was able to use the techniques and concepts I learned as a research assistant many years earlier to help complete the project.

Neuroblastoma is unique from many other cancers in that they can be pushed towards differentiation relatively easily. For example, in the clinic 13-cis-Retionic Acid (a vitamin A derivative) is used to treat neuroblastoma patients, as it can force neuroblastoma cells to differentiate permanently into peripheral neurons. Despite the success of Retinoic acid, high-risk neuroblastomas have very poor prognosis, and are less willing to differentiate. MicroRNAs can also drive differentiation, miR-124 has been shown to differentiate neuronal precursors. We hypothesized that transcription factors regulated by miR-124 were essential in neuroblastoma identity. Thus, we knocked down a network of transcription factors individually, and with differentiation as marker of importance, identified genes responsible for keeping neuroblastoma cells undifferentiated.

While we identified many genes important in keeping neuroblastoma cells as neuroblastoma cells, I identified ELF4, as one of the most essential genes. Even a temporary loss of this gene is enough for neuroblastoma cells to reprogram permanently into neurons. Furthermore, we found that overexpressing this gene can protect from differentiation therapies, such as miR-124 and retinoic acid. RNA-sequencing revealed that ELF4 controls cell cycle progression, through a specific complex known as the DREAM complex. Finally, we found a potential regulatory “feed-forward” loop, where miR-124 functions by not only targeting ELF4, but also many of ELF4’s targets, which may explain how miR-124 is able to cause differentiation so efficiently. Overall, we found that neurogenic miR-124 drives neuroblastoma differentiation partially through the downregulation of ELF4, and that ELF4 is essential for maintaining the identity of neuroblastoma cells.

What are your future plans?

Following graduation, I would like to continue my training and education as a post-doctoral fellow. Ideally learning a new field. Personally, I am huge fan of proteomics; however, the field is rather green, in comparison to transcriptomics, which I have done most of my training in. Long-term (if I’m lucky enough) I would like to climb the ladder of academia.

In Press is a section in The Pipette Gazette that highlights publications by students. To read more In Press articles, click here.