Unlocking the understanding of breast cancer with Dr. Giada Zurlo
We all know that breast cancer is one of the major causes of concern among women across the globe. To counter the menace associated with the condition scientists globally are working to find therapeutics targets. In the present interview, we would like to highlight the work of scientist Dr. Giada Zurlo, published as “Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple-negative breast cancer”.
Dr. Giada Zurlo is a passionate cellular and molecular biologist with 6+ years of experience in the identification of novel therapeutic targets. She is working as a research scientist at UT Southwestern Medical Centre.
The journey of Dr. Giada Zurlo
Dr. Giada Zurlo grew up in northern Italy, in a beautiful medieval walled town called Cittadella. After studying molecular biology at the University of Padua, her desire to travel and learn new languages took her to Paris, where she obtained a scholarship and earned PhD degree in physiopathology and therapeutic innovation at the University of Paris-Saclay. Her Ph.D. studies focused on a rare yet deadly pulmonary disease, pulmonary arterial hypertension, which is characterized by an excessive proliferation of muscular cells of the pulmonary artery wall. After Ph.D., Dr. Giada Zurlo moved to the US to continue doing research, this time on a more common disease, breast cancer, also characterized by uncontrolled cell growth. Specifically, She is now studying the role of cellular oxygen sensors, called hydroxylases, in cancer.
“When I am not in the lab planning and performing experiments, you can find me baking, playing with my 2-year-old son or hiking with my friends.” – Dr. Giada Zurlo
Let’s unfold interesting conversation with Dr. Giada and explore more about scientific research, women scientist and more.
Why breast cancer was the focus of your research work?
Dr. Giada Zurlo: We are interested in studying breast cancer because it affects a very wide population: breast cancer is, in fact, the second leading cause of cancer death among women in the US. In this work, we focused on a subtype of breast cancer, called triple-negative, which is characterized by the absence of three markers that are present and constitute a therapeutic target in the other breast cancer subtypes: the oestrogen receptor, progesterone receptor, and Her2. Since triple-negative breast cancer cells do not present these markers, no targeted therapy is currently available. Non-selective radiotherapy and chemotherapy are the available options, but most patients present residual disease after these treatments, with a high incidence of tumor spread and development also in other organs (a phenomenon called metastasis) and, therefore, a very poor prognosis.
Can you share some brief insight into the role of Prolyl hydroxylase substrate adenylosuccinate lyase?
Dr. Giada Zurlo: Adenylosuccinatelyase (ADSL) is an enzyme involved in the metabolism of DNA, the genetic information carrier. It has been well studied in the context of a neurological disorder called ADSL deficiency, caused by the lack of a functional ADSL and characterized by delayed mental and movement ability development, autistic behavior and seizures. However, the role of ADSL in cancer, especially triple-negative breast cancer, was completely unknown before our study. We show that the lack of ADSL in triple-negative breast cancer cells decreases their ability to grow and invade other tissues (lungs). We provide evidence that ADSL activity, important to mediate this effect, is modulated by a protein modification called hydroxylation. When ADSL cannot be hydroxylated, its activity decreases, causing a drop in the production of a molecule called adenosine. Adenosine, in turn, increases the level of a protein, cMYC, which triggers a cascade of events resulting in increased cell growth and tumor formation.
What were the turning points in your research work which help you draw the relevant conclusion?
Dr. Giada Zurlo: The first turning point was when we realized that the transcription factor HIF-1alpha, the most known substrate of the hydroxylase EglN2, was probably not responsible for EglN2 tumorigenic function in triple-negative breast cancer. In fact, when we reduced EglN2 in cells, no change was detected in the HIF-1alpha protein level. This observation led us to perform the screening for EglN2 substrates in the absence of HIF-1alpha, to prevent it to overshadow the potential other hits. Another turning point was when we found that ADSL hydroxylation changes its activity: this led us to hypothesize that the effect of ADSL on cancer cell growth was mediated by one of the products of ADSL enzymatic reaction. The hypothesis turned out to be correct: adenosine was able to mediate the ADSL effect on cancer cell proliferation.
As we all know doing research is not an easy task. What challenges did you face as a scientist?
Dr. Giada Zurlo: The main challenge of this research was the initial screening to find potential substrates of the hydroxylase EglN2. Hydroxylation is a very quick reaction that modifies a protein, thus altering its stability, activity or ability to interact with other proteins. Once the protein has been hydroxylated, it’s instantly released by the hydroxylase, making the detection of the substrates very difficult. We had to optimize a system to “freeze” the hydroxylase-substrate complex in order to find adenylosuccinate lyase. Then, of course, there have been other technical obstacles on the road: antibodies that didn’t work well, incubation times that needed to be adjusted, and so on. I’m sure other fellow scientists can relate to what I’m talking about. Fortunately, the only challenges were experimental: my mentor, Dr. Qing Zhang, is doing a great job in terms of getting enough funding for our research to continue smoothly, and I cannot thank him enough for this.
Being a woman scientist is something that is admirable as we all know about the poor gender ratio in the field. What excited you to pursue research? What will be your suggestion for women out there who wants to pursue similar career in research?
Dr. Giada Zurlo: I’m fascinated by scientific research because it’s dynamic, always evolving and never-ending. There will surely be a new question arising from every answer. However, even if you are exploring the unknown, you can count on landmarks that will support and guide you: the data. You take a new step once you feel the one you are on is stable enough. I think the beauty of exploring can be applied to all research fields, but I chose molecular biology because I would love my research to give even a tiny hint to ameliorate the current anti-cancer therapies.
To be honest, I luckily never felt being a woman was an obstacle in my career. I think everything depends on your expectations: if you are aiming at a quiet 9 to 5 job, research would not be for you, whatever your gender is. Research is beautiful but very challenging: behind one success there may be a thousand failures. Therefore, my suggestion is to ask yourself: am I crazy (about science) enough to pursue research? If the answer is yes, just go for it!
UT Southwestern Medical Centre is a renowned place you are working in, would you like to highlight something about the institution.
Dr. Giada Zurlo: UT Southwestern Medical Center is a top-performing institution: not by chance, no less than six of its faculty members have been awarded the Nobel Prize since 1985. However, I have been working in this exciting environment for only one month.
The work on adenylosuccinate lyase and cancer has been almost entirely performed in another America’s top research institute: Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill. I don’t think there are many other universities where you can feel such a collaborative and friendly atmosphere. It’s no hard job to get incredible help from other scientists from different labs, as well as from the several facilities on campus.