How does nutrition impact gene regulation? How does cellular metabolism impact cancer? Kathryn E. Wellen, PhD, an associate professor of Cancer Biology and principal investigator of the Wellen Lab, seeks to answer these questions to provide insight into the connection between metabolism — the chemical reactions that change food into energy — and cancer biology.
As a predoctoral student at Harvard, Wellen's research originally focused on fat tissue biology. She soon shifted her focus to cancer cell metabolism after learning more about how genes regulate metabolism in cancer cells.
"With a background in metabolic disease, I was intrigued by the idea that metabolism was also altered in cancer cells," Wellen said. "I wanted to understand how these changes supported tumor growth and might be targeted therapeutically."
This interest brought Wellen to the University of Pennsylvania, where she has focused on the field of cancer metabolism. In this Q&A, Wellen describes her current research, her challenges, and her opportunities.
What research are you currently undertaking?
Kathryn E. Wellen, PhD
My lab is broadly interested in metabolic signaling and metabolic adaptive mechanisms in cancer and physiology. Metabolic signaling is how a cell detects which nutrients are available, and adaptive mechanisms are the ways a cell responds to the available nutrients. For example, if in a cell’s environment, there is limited glutamine — the most abundant amino acid found in the body — the cell will change its metabolism to adapt to the nutrients it does have available.
We’ve had a long-standing interest in the bidirectional relationship between cellular metabolism and chromatin modification. Cellular metabolism refers to the chemical reactions by which nutrients are broken down to release energy. These reactions also generate intermediates that are used to build larger molecules like lipids, proteins, DNA, and RNA. Chromatin is a complex of DNA and proteins that organizes DNA in the nucleus and is important for regulation of gene expression.
There are different chemical modifications to chromatin — what’s interesting is that they are often derived directly from cellular metabolism. For example, we are investigating acetyl-CoA, which is produced through metabolism of various nutrients, and is needed for histone acetylation (a critical modification that changes chromatin architecture and helps activate gene expression). We found that chromatin modifications can be quite sensitive to changes in the metabolism of the cell and that this can be a way that cellular metabolism influences gene expression. We are working to further understand what this means.
This work has also led us into other related areas. We know that metabolic processes take place within the cell. Being able to study where exactly these processes happen within the cell is an important component to understanding many aspects of metabolism. Typically, a whole tissue sample or cell culture plate is used to measure metabolites — the intermediate or end product of metabolism. Metabolism occurs in a way that is very compartmentalized, however, so whole cell samples may not reflect the abundance of metabolite in the specific location you are interested in. With that in mind, we are applying new methods to study subcellular metabolite pools to uncover new insights into how metabolism talks to chromatin.
Finally, we have also become very interested in the impact of the body’s systemic metabolism on metabolism in cancer cells. In other words, how factors such as diet or systemic nutrient utilization impact tumor growth.
What inspired you to do the research you’re doing?
For me, it’s a mix of being able to pursue questions that I find interesting and the desire to do work that holds the potential to impact human health. This is what I find appealing about studying diet-cancer links — the potential to uncover dietary strategies that might improve therapeutic outcomes. But I also really like trying to explain cellular and molecular mechanisms of nutrient handling, building models as we accumulate data, and revising them as we test our hypotheses. I enjoy the puzzle solving aspect of research, particularly discussing data and ideas with my lab members!
What are the biggest challenges you face as a scientist? Where do you see the greatest opportunities?
One of the biggest challenges is that there is never, ever enough time to do everything that you want to do. Balancing family life, research, mentoring, grant and paper writing, reviewing, and teaching and administrative responsibilities can be very difficult since we all only have 24 hours in the day. However, I do find most of my activities very rewarding.
I see my biggest opportunity for impact in mentoring. I hope that my lab does impactful research — and we certainly strive to — but for me, my biggest source of pride is seeing trainees develop scientifically, and come out of the lab excited about science and prepared for the next stage in their career. I also care a lot about promoting a positive, supportive, and inclusive academic culture, both within the lab and within the institution.
Scientifically, I’m really excited about the potential for understanding at the mechanistic level how organismal metabolism impacts cancer metabolism. The possibility of being able to combine dietary interventions with other therapeutics to maximize effectiveness or reduce toxicity is very appealing, and I think this is a real opportunity for impact in the cancer metabolism field.