Parsing the Pathways

In the war against cancer, it would be great if all cancer cells used the same sorts of trickery to develop, grow, and spread. Unfortunately, they don’t. Various kinds of cancer cells use many different cellular pathways – cascades of interacting proteins inside cells – to cause disease and avoid the therapeutics designed to kill them.

In our continuing series of student profiles, we meet Kathleen Mulvaney, a fifth-year PhD student in the lab of Ben Major, PhD, who has dedicated the past four years to elucidating how the protein KEAP1 interacts with a cellular pathway crucial for cells to complete their cell cycle and divide to cause disease.

We sat down with Kathleen to discuss her history, her work, and why she chose UNC after a stellar research career as an undergrad.

Birthdate: March 6, 1987

Hometown: Buffalo, NY

Education: University of Rochester, BS, biology / PhD student UNC, 2010

Awards: honorable mention, National Science Foundation Graduate Research Fellowship program; Poster award, IMSD Symposium, Best Oral Talk

Dissertation: New Role for KEAP1 in Cell Cycle Regulation

Mentor: Ben Major, PhD, assistant professor of cell biology and physiology; member, UNC Comprehensive Cancer Center

Goal: Understanding the intersection of different cell pathways that cancer cells exploit.

Extracurriculars: hiking with her dog, reading, traveling, being a BBSP peer mentor

History:

“I’ve always been interested in science. I took advanced science classes in high school and knew, generally, that I wanted to go into science. I took international baccalaureate courses that help inner city schools offer a more holistic international kind of education. I wound up having a lot of opportunities to do research and attend lectures by PhDs from the local cancer institute. During my senior year, my father died of brain cancer, and this really directed me into cancer research.”

Undergraduate research

“I worked in a lab that largely studied the most common form of B-cell lymphoma. We profiled the different tumor cell lines and tried to look at two particular molecules – a transcription factor that controlled the amount of the second molecule, which coats immune cells. In normal biology, T-cells can trigger cell death in B-cells that are undergoing irregularities. But because B-cell lymphoma cells drop this molecule, T-cells can’t bind to the cancer cells; this is one way in which cancer cells survive. We were trying to use drugs to force the B-cells to re-express those molecules so T-cells could target them.

“We showed that class of drugs called HDAC inhibitors was able to up-regulate the transcription factor and thereby up-regulate the expression of a protein we were studying.”

As an undergraduate, Mulvaney wound up being the second author on one of her undergrad mentor’s papers, and third author on another.

Why UNC?

“I applied to UNC because it has a great umbrella program for graduate students [Biological and Biomedical Sciences Program or BBSP] and a great reputation. When I came here to interview, it really seemed as though UNC was stronger than the other schools I was considering when it came to training graduate students. When I came down here to interview, I just couldn’t believe how interested the PIs and other faculty members were in training students. Two students gave phenomenal talks during the interview weekend. It was very clear that people were taking a lot of time to train them and giving them opportunities to pursue very interesting and challenging projects.

“It’s been incredible here. The faculty members are so supportive, the TIBBS program had all these different initiatives to help us write grants and papers; it helps students apply for post docs.

“I love it here. The biggest issue is, yeah, I wish this exact university with all its assets was six or eight hours closer to Buffalo.”

Why the Major lab?

“When I rotated through Ben’s lab during my first year, I was immediately interested in in his research, including different, interesting research techniques. Also, I liked how he mentored students. He’s been very amenable to students thinking independently and creating our own projects and even our own technologies. He’s also very encouraging; we can apply for anything we want – grants, any career development awards for any type of career.”

What’s your current research?

“The overarching goal of the Major lab is to dissect cancer signaling pathways – the ways cancer cells survive and thrive. We do this mostly through mass spectrometry, which is a technique that allows us to know exactly which proteins are in a sample at a given time. This is essential in the study of cancer. If you want to know what a particular protein does in a cancer cell, a great way to find out is to figure out where the protein is in the cell and what it binds to. With mass spec we can very quickly find what the protein binds to.

“Using a more low-throughput technique, you can only ask if “this” one protein binds to “that” one molecule. But with mass spec we can find all of the things that a come in contact with one protein in different contexts throughout the cell. Then, if we treat the cell with chemo, a stress agent, or a DNA-damaging agent, we can see what happens to all the proteins that our single protein of interest comes in contact with. We can learn how these other proteins change during this process.

“This makes mass spectrometry a very powerful tool to understand which proteins are important for cancer cells.

“For the project I work on, we came up with 26 proteins that interact with the protein we study – KEAP1. We realized that one of those 26 proteins was a cell cycle regulator, MCM3. That was interesting because the cell cycle is so essential for cells to divide. Unregulated cell division is a hallmark of cancer. So, any way that cells are permitted to complete the cell cycle is interesting.

“My project has been focused on understanding why these two proteins interact and ultimately how does KEAP1 – which no one had known was involved in cell cycle regulation – help complete the cell cycle.

“We believe that KEAP1 – in a complex with other proteins – has catalytic activity to place the protein MCM3 onto DNA.

“MCM3 functions as a complex that unwinds DNA so that the DNA can be copied. Cells have to do this before they can divide into two new cells. Any way you can stop DNA from copying is potentially a powerful way to treat cancer.”

The Future

“I’m in my fifth year at UNC; I’d say I probably have another six to 12 months here. After a postdoctoral fellowship, I’d like to run my own lab. I’d like to keep coming up with new ideas to target cancer, to take all these great techniques and things I’ve learned at UNC and try to run a translational lab – a center of basic biology research that also does drug development and screenings in animal models.

“Ultimately, I want to create better ways to treat patients.”