Gina DeNicola investigates the metabolism of cancer cells in vivo with a focus on NRF2 and the tumor microenvironment.

Science runs through her veins. The daughter of a chemist, Gina DeNicola was a valuable member of her high school Science Olympiad team in Newark, Delaware. They won the state championship almost every year that she competed. Although her current favorite model organism is the mouse, Gina’s first experience with science came through her undergraduate research on muscle development with Dr. Susan Abmayr at Penn State University, where she worked with fruit flies. However, flies and Gina did not get along well. “I kept dropping the bottles and breaking them. I felt like the flies were crawling on me all the time,” she recalls. Gina then switched to studying mice for her PhD under the supervision of David Tuveson at the University of Pennsylvania, where she investigated the oncogenic signaling-driven regulation of the transcription factor NRF2. In her research, Gina showed that NRF2 is crucial for Kras-mediated lung and pancreatic tumorigenesis (1). Her work on NRF2 sparked her interest in tumor metabolic reprogramming, leading her to join the lab of Lewis Cantley at Weill Cornell Medicine to investigate the role of NRF2 in serine biosynthesis in lung cancer (2). Gina’s passion for NRF2 did not end there. After completing her postdoc, she opened her lab at Moffitt Cancer Center in 2016, where her research continues to focus on NRF2 in tumorigenesis and metabolism. Gina is currently the Interim Chair of the Department of Metabolism & Physiology at Moffitt Cancer Center and the Leader of the Metabolism Program. We contacted her to learn more about her scientific journey and future endeavors.

Gina DeNicola headshot. Photo by Nicolas Gould, Moffitt Cancer Center.

Gina, what interested you about tumor metabolism?

I became interested in tumor metabolism when I was studying NRF2 as a PhD student. NRF2 regulates redox metabolism, which is tightly linked to central carbon, iron, and sulfur metabolism, and other pathways. The concept of tumors hijacking stress-responsive pathways to support their proliferation and viability intrigued me. Even now, many years later, I’m still trying to understand how it all works.

What are you currently working on?

We are currently focusing on sulfur metabolism. When we began studying how NRF2 activation perturbs metabolism, we found that the pathways were dominated by cysteine-dependent metabolism. This made us realize that there were many questions to answer about how cysteine is acquired and used in tumors. Much of what we know about how cancer cells obtain cysteine comes from cultured cells in a dish, where some studies have shown that cancer cells can make their own cysteine. However, our own research revealed that lung cancer cells in culture cannot make cysteine. We spent a lot of time developing the expertise to follow metabolites in tissues and tumors in genetically engineered mouse models of cancer to ask how cysteine is acquired in diverse tissues and the tumors that arise from them. This process is complicated because it involves implanting a catheter in the jugular vein of a mouse and then infusing them for hours with a labeled amino acid to look at cysteine synthesis or uptake from the circulation. Using this method, we found that most types of cancers we profiled (pancreatic, non-small cell lung cancer, small cell lung cancer) cannot make their own cysteine and must rely on cysteine from the circulation (3). However, this method relies on the extraction of metabolites from a large piece of tissue, so we lose spatial information about metabolic activity in discrete cell types. In future studies, we plan to spatially resolve metabolic pathway activity in tumors and ask how starvation or therapy influences cysteine metabolism.

Infusion setup for stable isotope tracing in mice. Photo by Aimee Falzone, DeNicola lab.

Not always do cell cultures recapitulate the in vivo conditions…

At least not in the tumor metabolism field. With the development of stable isotope tracers, which are infused into animals or humans and then followed into downstream metabolites using mass spectrometry or nuclear magnetic resonance, the field has learned that nutrient availability and other cell types within tumors like immune cells or fibroblasts affect the metabolism of cancer cells. The complex tumor microenvironment has a profound effect on tumor metabolism, so studies in cell culture don’t always reflect what’s happening in vivo. However, dissociating tumors to isolate different cell types can rapidly change metabolism within the different compartments, so we still face technical challenges that prevent us from studying metabolism in cells in situ. Although we are moving toward it, we haven’t yet achieved single-cell resolution.

What kind of approach do you bring to your work?

Teamwork is a really important part of our lab culture. We have a diverse skill set in the lab that enables us to conduct a variety of research, from mouse modeling to animal surgeries and infusions, to mass spectrometry metabolomics, to molecular biology and genomics. While everyone has their own projects, they also collaborate extensively and train each other in these skills to accomplish goals.

Who were your key influences early in your career?

My two biggest influences are Lewis Cantley and Ralph DeBerardinis. Lew was very supportive of me as a postdoc and let me study whatever I wanted, even if it wasn’t the main focus of his lab. He also showed me how to be incredibly kind and generous as a scientist, which is what I most aspire to. I also credit him for turning me into such an outspoken person, because I wasn’t speaking up much in lab meetings when I was new to the lab; he told me, “I want to hear you.” Ralph DeBerardinis patiently taught me metabolism as a PhD student back when he was in Craig Thompson’s lab and was extremely generous with his data and time when I was a postdoc with Lew, and I also try to model my generosity after his influence.

In your experience, have you ever felt unprepared for running your own lab, and what did you learn from that experience?

During my postdoc, I gained a lot of experience writing grants, dealing with budgets, writing animal protocols, and mentoring PhD students, so I assumed running a lab would be a breeze. I was very wrong. I quickly realized that there were many different details to manage on a daily basis, and managing people was much harder than I anticipated. I hated managing people at first and was probably not very good at it. I tried too hard to be everything to everyone and viewed it as a personal failure when things didn’t work out. However, I learned that there are no inherently “good” or “bad” people; it’s all about finding the right fit. If the fit is not right, then it’s in everyone’s best interest to move on and find a better fit for both parties. I also learned that conflicts may arise in a group, but most of the time, it’s due to miscommunication, and talking it out can resolve issues quickly. Don’t let issues fester.

DeNicola lab photo wall. Photo by Gina DeNicola of Yumi Kim’s photo wall.

What has been the biggest accomplishment in your career so far?

Training the next generation! I am most proud when my students and postdocs achieve their goals and watching them go on to start their own labs, go to postgraduate schools, and find their dream jobs has made me really happy.

And what has been the biggest challenge to date?

I always had an excellent memory and consider myself to be a pretty smart person. However, in 2021, I realized I was really struggling with memory loss and concentration. Initially, I thought I was just getting old, but it turned out I had a benign parathyroid tumor. The surgery to remove it was straightforward, but the year or so that my brain didn’t work was really challenging for me. No one else noticed, though, which made me realize that we can be our harshest critics.

Wow, I’m sorry to hear that, and I’m happy that you have fully recovered. By the way, congratulations on being recently appointed as the director of the newly established Metabolism Program at Moffitt Cancer Center! Could you share more about the direction of this program and any new initiatives you plan to promote?

Thank you! I’m excited to get started. I’ve only been in this role for 3 mo now so I can tell you about my future plans. Our program will focus on host factors that influence tumor metabolism, such as age, diet, metabolic syndrome, the microbiome, and others. We plan on recruiting many faculty in this area over the next several years and will also be searching for a Clinical Co-Leader for the program, so please reach out if this sounds like you! In addition to our recruitment efforts, we plan on expanding our technology and training efforts to support the Program and add a new Cancer Metabolism major to our PhD program.

Gina, you also played a key role in promoting the Cancer Metabolism Showcase, a virtual conference that highlights the work of non-faculty scientists and provides them with career guidance. What inspired you to launch this initiative?

We started the Cancer Metabolism Showcase and Workshop (CMSW) after a major metabolism conference was postponed for the second time due to COVID-19, leaving a void in networking and presentation opportunities for our students and postdocs. We wanted to host a virtual conference for these junior scientists, but we realized we had the opportunity to do something different. We added a career keynote with career advice from a Senior Faculty presenter and workshops with career advice. We also offered it free of charge so the only obstacle to attendance was an internet connection, although the time zone does present challenges for some of our attendees—but the feedback has been very positive. Luckily, Moffitt Cancer Center and the Wilmot Cancer Center were willing to sponsor the event in Gather Town so we could do so, and Memorial Sloan Kettering hosted the Zoom.

Do you have plans to host the CMSW in person in the future?

We did discuss whether we might want to host it in person in the future, but we think that the virtual format makes it more accessible and inclusive and allows us to involve more speakers in the career development sessions. It is quite expensive to attend conferences in person, and there are other barriers like location or childcare. In-person events have important roles, but we think we can offer something different with this venue.

Finally, is there anything about yourself that few people know?

I have a black belt in karate, so I suppose you could say I have a hidden talent for martial arts!

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