Jason Pitarresi, PhD, is someone who knows what he wants. At an early age, he recognized his knack for science, set out to be a cancer researcher, and—in the blink of an eye—he became one.
Growing up and attending college in small upstate New York towns made access to large research organizations difficult, but he didn’t let that stop him. To get his start, he emailed scientists at the Roswell Park Comprehensive Cancer Center in Buffalo, NY, to find a volunteer position as a laboratory assistant. This Cancer Center is highly esteemed and accredited by the National Cancer Institute, making the 2-hour round trip drive a minor price to pay. He quickly became a trusted colleague, garnering a full-time position and keys to the lab.
This hard-earned experience gained during his college years helped secure him a spot in top labs for both his graduate school and post-doctoral training.
Arriving at the University of Massachusetts Chan Medical School in August 2022, where he directs an independent research lab, he tackles pancreatic cancer from multiple angles. High on his to-do list are uncovering mechanisms that make pancreatic cancer highly metastatic, finding ways to take it down, and mentoring the next generation of pancreatic-cancer scientists.
What drew you to Ohio State for graduate school?
At Roswell Park, I primarily conducted in vitro studies on mechanisms of apoptosis (cell death), but I wanted to learn in vivo techniques to study cancer in more human-relevant systems. At Ohio State University, I trained with a well-known scientist with expertise in using mouse models to study cancer. I was also attracted to the size of Ohio State, with many labs dedicated to studying cancer it was easy to find an expert on any given subject.
What questions did you pursue using mouse models?
I started out studying fibroblasts in mouse models of breast cancer and later switched focus to pancreatic cancer. Fibroblasts are “normal” cells that are recruited to tumors and are often co-opted by the tumor to make the disease worse. In normal physiology, the primary purpose of fibroblasts is to heal wounds. Tumors share many properties with wounds and cancer has been described as “a wound that never heals.” So fibroblasts gravitate toward them, becoming part of the tumor’s niche or microenvironment.
However, not all fibroblasts carry out the same tasks in tumors and there is likely fibroblast heterogeneity within tumors. Some fibroblasts can promote tumor cell growth, while others hinder it. We used mouse models to explore which variables dictate fibroblasts’ fate and ultimately found that certain types of fibroblasts were suppressing the tumor’s growth. This became critically important in the context of fibroblast targeting therapies, which I focused on during graduate school.
How did you use your post-doctoral years to expand your skill set?
With a solid understanding of tumor-adjacent cells, like fibroblasts, in my grasp, I wanted to flip the table and study epithelial tumor cell biology. I went to the University of Pennsylvania (UPenn) to study a form of cellular plasticity known as epithelial to mesenchymal transition—or EMT—one of the primary drivers of tumor metastasis.
Epithelial tumor cells form tight junctions with neighboring cells and their primary goal is to proliferate, while mesenchymal tumor cells lose some of these features and instead prioritize migration and invasion. The latter properties are needed for cancer to spread and metastasize, and I spent my time at UPenn building new mouse models to uncover drivers of the metastatic process as cells undergo EMT.
Pancreatic tumor cells are labeled with yellow fluorescent protein (YFP; shown in green), surrounded by fibroblasts in magenta.
What tools did you use to investigate cell plasticity and EMT?
We first used RNA sequencing techniques to uncover the molecular properties of tumor cells as they underwent EMT. By doing so, we could better understand what drives pancreatic cancer metastasis and hopefully widen therapeutic opportunities. But this is tricky to study in vivo because as epithelial tumor cells transform into mesenchymal ones, they lose their telltale protein marker, E-cadherin. Without this tag, it is difficult to distinguish tumor cells from other cells—such as fibroblasts—that make up the microenvironment. To effectively select all the tumor cells for analysis, we needed a way to differentiate them from non-tumor cells. Genetic lineage labeling provided the perfect solution to this problem. This method offers a way to fluorescently label all tumor cells and their descendants so that we can track them no matter what state they are in—epithelial, mesenchymal, or something in between. It gives us a sure-fire way to select tumor cells–and only tumor cells–for downstream analysis.
What did genetic sequencing reveal about pancreatic tumor cells?
We first built a mouse model where we could selectively turn on the EMT program and drive metastasis. When we analyzed the molecular properties of these highly metastatic tumor cells, we found that they expressed elevated amounts of a protein called PTHrP. A protein never before associated with pancreatic cancer metastasis.
What about this discovery fuels your hope for impacting patients down the line?
We targeted this protein with a drug, in both mice and 3D organoid pancreatic cancer models, and the tumors shrank. More importantly, we dramatically extended the lifespan of our pancreatic cancer mouse models when they lost PTHrP, either through genetic deletion or pharmacological inhibition. We attributed this success to the ability of anti-PTHrP therapy to block metastasis. We also found that abnormally high levels of PTHrP are found in about 1/3 of pancreatic patients and that it may be a marker for a highly aggressive subtype of pancreatic cancer. We hope to translate our pre-clinical mouse modeling results into a clinical trial to one day help pancreatic cancer patients with this disease.
What is the most enjoyable part of your job?
I love mentoring trainees. During my own training, I was always willing to mentor students and found that I had a real passion to teach people how to build a career around research. I'm passionate about guiding the next generation of scientists and hope that I can foster a great research environment for my trainees to achieve their goals.
About Jason Pitarresi, PhD
Jason Pitarresi, PhD, is an assistant professor in the Department of Medicine, Division of Hematology-Oncology at the University of Massachusetts Chan Medical School and the Department of Molecular, Cell, and Cancer Biology. He earned his PhD in Biochemistry from Ohio State University. He is a 2023 American Association of Cancer Research NextGen Star and a recipient of the National Institutes of Health Pathway to Independence K99/R00 Award.
