First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Rodanthi Lyraki is first author on ‘ Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice’, published in DMM. Rodanthi conducted the research described in this article while a postdoctoral Fellow in Andreas Schedl's lab at Université Côte d’Azur, Nice, France.
How would you explain the main findings of your paper to non-scientific family and friends?
Gender often defines how vulnerable we are to certain diseases. For example, some types of cancer are more frequently diagnosed in female compared to male patients. Many factors, such as our DNA, hormones or even societal influences and learned behaviors, may play a role in this difference. We found a striking example when studying the adrenal glands – hormone-producing organs that regulate blood pressure, stress response and other functions essential for survival – in laboratory mice. When researching a specific genetic alteration linked to adrenal cancer, we found that increased levels of male sex hormones named androgens suppress the tendency of the organ to grow bigger than normal. Using classic genetic techniques, we identified that androgens activate a specific protein in adrenal gland cells, which blocks the cell's tendency to divide and grow the organ. Since similar processes are paramount in the development of adrenal cancer in humans, our study provides a new framework for understanding why this type of cancer is much more frequently diagnosed in female patients.
“[...] our study provides a new framework for understanding why [adrenal] cancer is much more frequently diagnosed in female patients.”
What are the potential implications of these results for your field of research?
The influence of sex hormones on adrenal cortex physiology has long been recognized in the endocrinology field, and our team has studied this phenomenon before it had been related to stem cell activity. What stands out in our present study is the demonstration of this influence in a disease model, i.e. in adrenal hyperplasia caused by dysregulation of the WNT/β-catenin signalling pathway. The revelation that androgen treatment can suppress adrenocortical hyperplasia may have therapeutic implications in the future; however, we will need to find a way to administer these compounds safely and avoid secondary effects to the highest possible degree. Finally, our study provides other scientists with some mechanistic understanding of this phenomenon, as we demonstrate that it is due to androgen receptor activity in the adrenal cortex itself, and not linked to secondary effects from the hypothalamus and pituitary gland.
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
Our experimental system was the laboratory mouse. Using an animal model has allowed us to study adrenal cortex physiology in the context of an organism; this is important because the adrenal cortex is not acting in isolation but as part of a network called the hypothalamic-pituitary-adrenal axis. We have also been able to use a variety of elegant genetic techniques that are available to us, thanks to many years of genetic research involving this model. However, we firmly believe in the principles of Replacement, Reduction and Refinement for animal models in research and we advocate the use only when strictly necessary. Now, the way forward for the field is undoubtedly studying human samples and exploiting the databases available for adrenal cancer patients.
What has surprised you the most while conducting your research?
Despite the striking morphological changes to the adrenal gland induced by the genetic manipulation of Wnt/β-catenin signaling, we neither found respective changes in adrenal hormone levels in the circulation nor any life-threatening complications to the model's overall survival. This observation certainly surprised me and reminded me of the extraordinary capacity of mammals for adaptation and regulation to maintain their homeostasis.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
Adrenocortical carcinoma is a rare disease, affecting around one in a million people in the US. Moreover, as not all patients have the same driver mutations, personalized treatment plans must emerge for every subtype of this disease. We expect to see an explosion of potentially life-saving treatment tools emerging in the next 10 years for many rare diseases. However, funding to pursue these treatments is lacking, as rare diseases are rarely profitable. More generally, governments and funding bodies should be made aware that every advance in a field of research will inevitably diffuse into other areas, and will have many far-reaching implications other than a narrow-minded calculation might suggest.
“We expect to see an explosion of potentially life-saving treatment tools emerging in the next 10 years for many rare diseases”
What changes do you think could improve the professional lives of scientists?
I believe in the value of a permanent network of support staff (animal caretakers, technicians, laboratory managers in sufficient numbers) in all research structures, who significantly facilitate the professional lives of scientists and save time for research-oriented activities. A postdoc or PhD student cannot accomplish every step of their project alone!
What's next for you?
I am looking for my next project in my field of interest: innovative therapies for endocrinological diseases. I am also an aspiring scientific writer.
Rodanthi Lyraki's contact details: Université Côte d’Azur, Inserm, CNRS, Institut de Biologie Valrose, 06108 Nice, France.