Student writer: Ava Daniel
Student editors: Mason LaMarche, Ava Daniel, Rita Chakrabarti
23andMe editor: Thao Do
Born and raised in Italy, Dr. Katerina Politi traveled to the United States after her undergraduate years to continue her studies in genetics and developmental biology. After completing a post-doctoral fellowship at the Memorial Sloan-Kettering Cancer Center, she became particularly interested in studying lung cancer. Joining Yale University’s faculty in 2010, Dr. Politi is now an Associate Professor in the Department of Pathology and the Yale Cancer Center, and the Principal investigator of her namesake laboratory. Dr. Politi focuses her research on lung cancer and the molecular determinants of sensitivity and resistance to lung cancer therapies.
How did you become interested in genetics?
My first real interest in genetics came from learning about it in high school, specifically about the types of experiments that one could do to figure out different important processes in genetics. I remember being completely fascinated in my biology class when my teacher explained how DNA copies and replicates itself, and the different mechanisms of how it does so. I learned about a lot of other experiments, as well, that tell us so many different things about genetics, and that was really why I became so interested in genetics. I think it definitely inspired me to study genetics at university, as well.
How and why did you decide to become a principal investigator?
I really followed what I was interested in and passionate about studying. I wanted to be able to pursue the scientific questions that I thought were important and interesting. I loved the possibility of working with people that came with different perspectives and angles, and could all contribute to answering the questions we were trying to ask. One of the great things about being a principal investigator is the flexibility and opportunity to work on the problems that mean the most to me, and that interest me the most. That’s something that I really cherish every day.
How did you first become interested in studying cancer?
I was always very interested in cancer. I think one of the bigger moments that made me realize that I really wanted to study it was when I spent a year at UNC-Chapel Hill … and I was taking classes there… and I remember hearing about the cancer resistant gene P53 and just being amazed—during the year that P53 was molecule of the year, in 1993. To me, it was absolutely amazing that there could be this protein in the cell that could have so many different functions that could be so important.
P53 is an important molecule in the cell… called a tumor suppressor*, and it is very important in controlling what happens to the cell… like whether the cell dies, or lives, or divides. So, when you actually lose this gene or when it is not functioning properly, it can contribute to developing cancer.
I understand that a large focus of your lab is looking at lung cancer resistance mechanisms. Can you talk more about that?
About 13-14 years ago, we really started to gain a better understanding about how some of the genetic alterations in tumors, and in lung tumors specifically, can be really important for the growth of those tumors. But, more importantly, some of these genetic changes can be targeted by specific drugs that can block the activity of those specifically altered proteins. These are called targeted therapies, and these therapies are a little bit different than your normal cytotoxic chemotherapies that are less specific. These are more targeted for the cells with these specific alterations.
We became more interested in these types of tumors that have these alterations as time went on, and as we continued to discover more about its behavior. We also realized that when patients are treated with these targeted therapies, then the tumor may initially respond and shrink, but then it eventually starts to grow back, as it becomes resistant to the therapies. I’ve been really interested in how—and there are lots of “how’s”—tumors become resistant to these therapies, and how they evolve and change over time in response to different therapies. This has been very interesting from the point of view of learning more about targeted therapies so that we can ultimately develop and improve them.
More recently, actually, new therapies that target the immune system have been shown to have efficacy in fighting and treating lung cancer. This is a big focus of the research of my laboratory. By understanding how these tumors become resistant, then we can figure out ways of targeting this resistance, which will ultimately lead to being able to properly attack cancer cells. This could be monumental, once we figure out how to optimize therapies.
How are you able to identify genetic modifications in these tumor cells?
We can use new sequencing technologies that allow us to study the sequence of hundreds of genes in the tumors. By using this approach, we can identify genetic modifications that are present in the tumors. This is a quick and efficient way to identify what we need to study.
Do you have any notable findings thus far?
Actually, I can tell you about something that happened very recently! We just published a paper a couple weeks ago—which was an incredible team effort here at Yale in which we showed that in lung tumors, one of the mechanisms to their development of resistance to immunotherapies is the loss of a specific protein that is important for the tumor cells to be recognized by T-cells*. These proteins act as identifiers for the cancer cells to hook onto, and from that point, the immunotherapy can directly target it. But if the tumor cells do not have these identifying proteins on the surface, they cannot be recognized by these T-cells and then become invisible to the immune system and to the immunotherapies. This causes the tumor cells to go completely undetected by these therapies, making them useless. All because one little protein is not present!
What impact do you hope your research may have in the broader context of medicine, genetics, and genetic contributions to disease?
One of the things that we’ve learned over the past decade or so is that knowing some of the molecular alterations there are in tumors is helpful in certain cases to direct the type of therapies a patient should receive. Based on what molecular subgroup the tumor is in, for example, we can figure out what kind of therapy a patient should be given. That is really a revolutionary development and has already transformed a lot in the context of medicine. This enables us to optimize the type of treatment that patients can get. I think that as we really learn more about the impact of different genetic alterations in tumors, it will help us to determine what kinds of therapies are best for certain tumors. It helps us with precision medicine*.
Even so, genetics isn’t the whole story, there are a lot of other aspects that we can build off of. For example, we can figure out the expression pattern of different tumors and different tumor cells in the body, and how tumors can change in terms of signaling, and so forth. There are many different layers, but the more we understand about these layers, the closer we will get to personalizing treatment for patients.
As a professional woman in the STEM field, do you have any advice for young women who wish to pursue a career in STEM?
Yes, absolutely! To go for it! Join us! Never be dissuaded. We need as many passionate people in the field as possible!!
Do you have any undergraduate researchers in your lab? If so, how are they involved in the research your lab conducts?
We do! Over the past years I have been at Yale, we’ve had many undergraduates that work with us. They work on projects that we tailor, depending on the individual, depending on what they are interested in, how much time they can give, and things like that. They are very helpful to our team and seem to enjoy themselves!
*Vocabulary
Tumor suppressor: A tumor suppressor is a protein that inhibits cancer growth, somewhere along the path of cancer progression. They work by slowing down rapid cell division, either by fixing a certain DNA mutation or by causing a rapidly growing cell to die.
T-cells: T cells are like soldiers who search out and destroy the targeted invaders for the immune system. The “T” stands for “thymus,” which is the organ where these cells mature.
Precision medicine: a medical model that proposes the customization of healthcare, with medical decisions, treatments, practices, or products being tailored to the individual patient
Notable papers published by the Politi Lab:
Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.
Genome-Wide RNA Interference: Functional Genomics in the Postgenomics Era.