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A Closer Look at the Evolution of Breast Cancer Cells

Dr. Kornelia Polyak shares the impact of understanding breast cancer at a molecular level

The immune system plays a critical role in tumor growth by attacking cancer cells with white blood cells. Cancer cells that survive this immune attack can become invasive and metastatic (a process called immune escape).

Dr. Kornelia Polyak’s groundbreaking and interdisciplinary breast cancer research has worked to address this. Her work has ranged from studying new prevention techniques to exploring metastasis to better understanding treatment resistance. Her goal is to understand the role the immune system plays in the evolution of breast tumors. And that’s why her lab is dedicated to the molecular analysis of human breast cancer.

Dr. Polyak, a BCRF investigator since 2008, is an internationally recognized leader in the breast cancer research field. She is a professor of medicine at Harvard Medical School, principal faculty at the Harvard Stem Cell Institute, and co-leader of Dana-Farber/Harvard Cancer Center’s Cancer Cell Biology Program.

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Read the transcript below:

Chris Riback: Dr. Polyak, thanks for joining me, I appreciate your time.

Dr. Kornelia Polyak: Thanks for having me, and thanks to everyone for joining us today.

Chris Riback: Yes, I'm grateful to the listeners as well. Let's start at what must be the very basic for somebody who wants to understand you and the work that you do and have done. What does it mean to be dedicated to the molecular analysis of human breast cancer?

Dr. Kornelia Polyak: What it means, very simplistically, we basically want to understand why women get breast cancer, why some progress to advanced and treatment-resistant disease, and what can we do about it. I've always been a very rational person, and I want to understand what's causing the problem, because I feel like that's the way we can solve it. So, I really want to know the molecular basis. So, how cancer starts, how does it progress? Why are they not responding to treatment, and then how can we prevent the process and also treat patients better?

Chris Riback: And that last part of what you just said is one of the areas that I wanted to ask you about. How do you think about preventing breast cancer as opposed to treating breast cancer?

Dr. Kornelia Polyak: Well, we all know that the biggest impact of any disease to reduce mortality and morbidity would be to prevent the disease. I mean, we're always advocating that, for if it can become prevented. So, in a way, we all know that it ideally would be best not to have breast cancer, and when people tell me that way, I would not have a job, I tell them I'm very happy to do something else with my life.

Anyway, prevention has the biggest impact because then if we don't have breast cancer, then we don't have to worry about progressing and treating, and we would save a lot of people's lives, and also we would reduce the morbidity associated with it.

That would be the ideal goal with breast cancer. But of course, it's not so easy to achieve that goal. It's a very challenging area from the scientific point of view, but also from the medical point of view to try to apply any prevention strategies because it has to be very safe. It has to be applied to the right person at the right time. And we know that for example, breast cancer risk may be determined in your young adulthood, maybe even during puberty. So it's not easy to decide when would be the best to apply that treatment or prevention strategy and how. And then also how we can identify people who are related to high risk of breast cancer.

The second-best option for having an impact on morbidity and mortality is early detection. Because the earlier we are diagnosed with cancer, the more likely we have it in a stage when it hasn't spread and more likely to respond, to treatment. So breast cancer, I would say, is actually one of the cancer types where we know, we have examples for prevention. I mean, we know that for example, the high-risk women can have mastectomy, which is not ideal, but at least we know that that can reduce the risk.

And then also we have screening strategies for the mammograms, as much as they are imperfect, but it's still a screening strategy. And, we diagnose people at early-stage disease and that has the biggest impact on improving mortality. So I think those are the two areas that I'm really passionate about, but it doesn't mean that we don't care about people who already have advanced-stage cancer, but ideally we would like to reduce the number of those patients, by having prevention and earlier diagnosis at larger numbers.

Chris Riback: So let's talk about molecules. What is immune escape?

Dr. Kornelia Polyak: Immune escape basically means that we have our immune system that's working to protect us from many diseases, a lot of infectious diseases, but at the same time also ensuring that we don't get cancer. So if you think about it, despite the fact that breast cancer, other cancers are, fairly common, it's still pretty rare if you think about how many cells in our body we have, and also how long we live.

It's very rare for somebody to have multiple different cancers in a lifetime. So in our immune system is one of the most effective, defense against infectious diseases, but at the same time also against cancer. And we think that many early cancers that actually, eliminated by the immune system or they don't become symptomatic.

But then cancers escape from what we call immune surveillance, which is basically like the immune system tries to recognize what doesn't belong to your body. What is looks abnormal and eliminated, and then cancers as they, grow or progress, they figured out a way how to overcome this immune defense. And that's what we call immune escape.

So we and others have shown that, as the tumors progress, we see a progressive decline in the active immune cells in the tissue, suggesting that somehow, either the cancer cells kind of not recognized properly, or they figured out a way how to suppress the immune cells in a way that they cannot be attacked and eliminated. So that's what the immune escape is.

Chris Riback: Am I understanding you to say that, in a sense, are there two questions? One is, is it that the white blood cells, or the immune system, is not able to sufficiently address the underlying cancer or precancerous cells? Or is it that somehow those underlying precancerous cells, and please you'll correct me that the parts that I'm getting wrong on this.

But that somehow those cells are able to evade or avoid the white blood cells and the immune system. Is that one of the questions that you are seeking to address is which side is the problem on? Is it on the immune system, or is it on the precancerous cells' system?

Dr. Kornelia Polyak: Yes. So actually, it can, both sides can happen and both sides are happening. Because for example, one way the cancer can avoid the immune cells or a white blood cell swarm eliminating it, is that it grows in a shielded environment. For example, early-stage breast cancer grows within the duct.

For some reason, immune cells cannot enter the ducts. So the question is, it's kind of almost like a physical barrier that forms around some of the cancers that makes the tissue too stiff and too kind of, dense for the immune cells to infiltrate. So that's one thing that can be happening and we know it's happening in some cases.

At the same time, the cancer cells can themselves produce suppressors of immune cells. For example, this immune checkpoint that probably many of you heard PDL-1 is one of those immune checkpoint proteins.

They can be produced by the cancer cells. They can be also produced by some kind of, white blood cells that are actually promoting cancer. So then the cancer cells can do it directly or indirectly by recruiting more suppressive cells. For example, there are, different types of macrophages, which are some of those cells that phagocytes, eat like other tissues. So some of those can produce immune-suppressive, molecules, and also a lot of these traumas, tissues that some cancers recruit again, they can produce a lot of those.

We think both of those can happen. It can even vary in one patient at different stages of progression or treatment, and also could vary depending on the different regions of the same tumor or different lesions in the same patient. So, that's why it's kind of so complicated and could be very unique at the particular stage to a particular person.

Chris Riback: How important is it to be able to research the cells? In the area, in the place where they originally are? Which I know is a core part of your research?

Dr. Kornelia Polyak: I think it's very important, because spatial location, like where are the cells in the tissue. It’s incredible information. So there is a good analogy that I've seen somebody present in a talk that I really like, because, if you think about it, like you eat a meal and somebody gives you a shake and, you don't know what's in the shake. You try to figure out that you're like mixed up apples, oranges, and so on. So you can, there are some molecular tests that could tell you that.

Nowadays we have molecular tests that would tell you every single cell in a tissue. What they are. There are the single cells, just profiling of the tissues, but you need to be so shaded for that. And then there are the set of technologies, one that we have been using and really, believe it's important is that not just the composition of their shake or, like the tissue, but you also know which cell is where.

Where is the cancer cell? Is the cancer cell next to the immune cell or the white blood cells? Or what of cancer cells are next to each other? And what are they doing?

Why do you see a particular pattern? So, this is a very fascinating area because we have an explosion in technologies. Like I've been in, breast cancer research for 20 years. And I always feel like every five, 10 years, we have such a technological advance that just makes you like, "Wow, now we can really understand things." So that's happening now. We see so many of these very detailed, single-cell methods, including insight to technologies like we can do sections tenets, see every single cell we can get full transcriptome.

Meaning like hundreds of genes expressed in a particular cell. And we know where they are, what is the location? What do they express? And even more, we also, testing technologies that would give you preserved the horse 3D architecture of the tissue. And see you, the cells in a three-dimension that are these technologies now core, the clear sheet microscopy.

So there are advances just at the molecular front and also the imaging front and the competition. Because, we are using machine learning and artificial intelligence to have the computer look at these images, because honestly, even a very experienced pathologist or people in the lab, we can be biased.

We are all human, we can be very well trained humans, but we're still human. We have a certain error rate. And we also don't recognize patterns. If you have to think about recognizing a pattern that you have thousands of different variables, we're not good at that. You know, we can recognize a couple of colors, but not that, but the computer, we can train them and say like, "This pattern comes from a patient that doesn't respond to treatment. Can you recognize it in another patient? And tell us, is this person likely to respond or not?"

I think the combination of the experimental methods, the computational methods and the microscopy imaging, it's all coming together to really allow us to dissect tumors and even how CT shoes at the depth that we never been able to do before.

Chris Riback: And tell me what study, what research do you have going on right now that we should know about, around this area or in a new area that you may be, pushing forward on?

Dr. Kornelia Polyak: Our lab studies the progression of breast tumors. Like starting from the very early stages and even some prevention studies. I can just give you a snippet of what we're doing, but at the same time, we also studying the late metastatic tissues, because I feel like we’re studying the evolution of the tumor with which goes from start to late-stage treatment-resistant cases, because we want to help everybody.

For example, in our prevention study is one thing that we're very excited about is we able to eliminate, the progenitors, the cells from which cancer would start and eliminate it, and then we can prevent cancer from ever forming. So that's one of the areas we're very excited because I feel like if we would do that in woman, then we don't have to have a mastectomy, because we just eliminating the cells from which the cancer would start out and we have the same effect as having good compete mastectomy.

That's one of the areas we're very excited. The other area that we're very excited about is the role of the immune system and the immune escape and when does it happen? And we think that it really happens at an early stage, what we call this Dr. Carcinoma insight two. For the reasons that I already kind of highlighted that at that stage, the tumor is still within the duct, so it hasn't started spreading and it. In a way it's shifted, but once it starts spreading in a body, then if it would not have the immune escape, then it would be likely to be destroyed by the immune cells.

And one thing that we have been, studying that when a tumor starts to develop in the tissue, even when it's a localized tumor, it can have some systemic effect. For example, you can have a breast tumor growing, but your bone marrow cells, or your lung stromal cells, supportive tissue cells, somehow getting signals from that cancer that makes them behave differently to be more permissive for cancer growth.

So we innovate with saying that metastatic process and metastatic development starts much before we can actually see metastatic lesions. And part of it is these factors that are secreted by the tumor cells, in the tumor. And many of those seems to educate the immune system in a way that don't recognize the cancer cells or allow them to grow at sites, they would not be growing. So we're trying to figure out when can be detected. Can we really detect it very early?

And can we recognize these women at early, even before they have metastatic lesions? And somehow interfere with this process in a way that they would never have metastatic lesions that would be clinically symptomatic.

Those are the areas. And then the third one is we are focusing on, treatment-resistant disease. Breast cancer, many women are fortunately responding well to treatment, like particularly, hormone receptor positive and her two positive disease. And even in triple-negative disease, you know?

Chris Riback: Yes.

Dr. Kornelia Polyak: More than half of patients respond well, but then we still have a large number who don't. And we're trying to understand why, why are they all resistant? Is it because of the tumor is very diverse, meaning like many different types of cancer cells very early on? Or we studying the tumors as kind of an equal system? Because tumor is not just the cancer cells, it's a community of cancer cells that form their little environment. And again, I already mentioned that there are these systemic changes occurring in patients, that or seem to be supportive of cancer.

We want to understand that. And of course, we also want to have better therapeutic strategies, and we all know that combination therapy is the best. Because when you have a combination of therapy, then you have the lowest likelihood that you have a subpopulation of cancer cells that resist that therapy. But it's not easy to develop these combination therapies because of course I could tell you like five, six different drugs that you combine, and then you're likely to kill all the cancer cells, but unfortunately you likely to harm the patient also.

Because the more drugs we mix, the side effects and the interactions of the drugs can be more serious. So it's very challenging to develop these combination therapies. So we using the computational and mathematical modeling approaches. And again, studying tumors as an ecosystem to develop these combination therapies and also figure out what time is the best to apply those early on.

Many times, I feel like many of our clinical trials for early agents are done in metastatic disease, which is very late. Many therapies may work better if you're doing it earlier. And I know that is a push for example, immunotherapy to apply earlier because you know, it may be more effective. So those are the three major areas that we're focusing on prevention, why do you get cancer? How they progress, how they escape the immune system. And then lastly, the therapies. Like how can we have better, more effective and less toxic therapies.

Chris Riback: You are active and the whole spectrum really from the beginning pre beginning stages, it sounds like, through to the therapies that you just discussed. And as you think about your work in those three stages, what frustrates you? What keeps you hopeful?

Dr. Kornelia Polyak: What frustrates me? Well, one of them now we have a fear about losing the young, talented people. That kind of not just frustrates me, it's kind of scares me because we need young, talented, smart people in science and medicine to make progress because as much as what we can do, we need the next generation. We need to train them.

Especially now, it's very challenging, the COVID makes everything is even more challenging. It's not easy to do academic research. It's the funding. It's not easy, it's many of the studies we do are long term. We're not talking about a year, but many of our projects that we working on and finally publish a paper, it takes like four or five years.

So training for the people is several years. The number of jobs for academic faculty is right now, very difficult to get. So I'm worried about having the young generation discouraged, from getting into science and, and not to mention that for example, many of our trainees are from other countries. The U.S has been, really taking advantage of providing an outstanding training environment for many students and even postgraduate trainees from different countries, who come here and then many of them go back to their country.

And that seems to be now jeopardized somewhat by the political climate of the U.S and the world also in general. And of course, COVID right now. So that's one of the challenges, the training and the next year generation. Then COVID now puts a challenge on us, on how do we interact and funding.

I know many, foundations and everybody's losing money. So that's going to be the next few years, not going to be easy to continue and support research. Which kind of in a part. Even the NCI director said that, "We just had such a positive impact on cancer. Mortality has been going down and we all fear that this kind of challenging time now because of the COVID situation and the economic turnaround, and then people not going for screening and all that, that will, change that."

Meaning we may actually see an increase or gain in cancer mortality. So that is the funding and not losing the faith in science. I think we really need to have people realize that science is our future in a way that that's how we solve problems.

We really need leadership at every level that supports science and research because we know, but we need data. You know, anybody who tells me they have an idea and they make a conclusion without data is not a real scientist. So we have to have people who recognize and support science and know how science works.

We can’t do magic, as much as I wish I could, but that's not how we do. We need data. We need to, have conclusive data, which means that not everything like anecdotal evidence is not real science. So that's a big challenge, I think for the whole world, in terms of like, we need to be supporting science at every level and making sure to be making progress. And, I would say that those attitudes are the two biggest challenges to funding, the training and also for the general public to be supportive of science.

Chris Riback: Yes. It certainly is a current topic across a whole number of scientific areas. What about on the hopeful side? What are you seeing from your research that keeps you hopeful?

Dr. Kornelia Polyak: We have such a convergence of technological advances, computational advances. And very enthusiastic committed group of people who working together as teams. We don't have individuals now, we have teams that includes mathematicians, clinicians, pathologist, research lab-

Chris Riback: Interdisciplinary.

Dr. Kornelia Polyak: Interdisciplinary, I'm just working on one DOD grant. But our whole research, if you look up our papers, we always have been working with, pathologists clinicians, computational biologist and epidemiologist. We really have a teamwork and we are working together with talking to each other.

First of all, nobody can do everything. And second that's our strengths that we have. People with different expertise that also comes with a different view of, seeing the problem and asking questions. So I think that the technology is the integrated nature of science. Those together, I think gives me hope that we will figure this out.

Chris Riback: And as we close the conversation, you mentioned a moment ago, the allure that the U.S education system has had over the years for students, who have come here internationally. I happen to be talking to one of them. Growing up in Hungary––was it always science for you? Was there a different interest? Did you always know, maybe you didn't know it was going to be coming to the U.S but did you always know it was going to be science?

Dr. Kornelia Polyak: Yes. I have to say I was an unusual child. I just loved science from very early stage. And my mom could tell you that I just loved like dissecting things. And I always wanted to understand things. And I loved reading books and I love doing, experiments. Some experiments, even at young age. And my family, and also growing up in Hungary, they were very supportive of science and allowing me to do extracurricular activities to, do more than the regular curriculum and, I'd be very thankful for the teachers who always sometimes are frustrating because they said, "Oh, you know, like you don't deserve an A, because you could have done more."

Which as a child, you don't always appreciate, but in reality, you need people who kind of push you and challenge you to see the most, what the most you can get out of yourself. I always kind of, was of course enthusiastic about science and math. I think in high school is when I really knew I want to do molecular cancer research. And this was in the 80s, when I was in high school, and I started reading books about molecular genetics. And, we had a very supportive high school.

It's somewhat kind of almost like college here. Like I could take major subjects. I finished the biologic curriculum early. My teacher arranged me to go to the clinic, actually the pathology and learn about the tissues and diseases at very early age. And then I kind of felt like this is what I want to do. And then as you know, in European system, we go to medical school straight from high school it's different way of training.

So when I, when I went to medical school I was 18, but I kind of wanted to do research, and experience what research is like. So as a medical student, I started working in a research lab. And again, this was in the 80s, so it was still molecular biology, which very not that developed in late 80s. But I happened to be lucky to work in a Hungarian National Academy lab. There's only one. Hungary is a small country. So there's only one institute and it happened to be right next to my medical school. So they let me work there as a medical student. And that was the time where PCR was discovered, the genes were discovered and all these very basic things in the late 80s. And I just, I was fascinated by that.

And then I knew that I want to pursue cancer research at the level that, very few places could do it in Europe. I'm in Hungary. Again, it's a very small country. It's like New York city when you think about it. The whole country is the size of that.

I could not do that kind of cancer research. So I applied for graduate school and I actually, I was at Cornell/Memorial Sloan Kettering, so close to you in New York. And, I happened to have a fascinating and amazing, graduate training that you can only imagine. For a student, because I worked with Joan Massagué at Sloan Kettering and discovered P-27, which is an inhibitor of cell.

It was a major discovery. We were in The New York Times. And also I felt like I can have an impact. I can actually discover things that will have an impact. So that kind of hooked me staying in research because after medical school training, I did do the exams to think about doing residency and fellowship training. And then I just felt like after being in a lab that this is what I want to do.

But in a way that I work with the clinical people and we work together, but the only step I don't do is I'm not treating the patients. And then the other major impact on my career was training with Bert Vogelstein as a post doc at Hopkins. Who I call the real, the father of cancer genetics. He's a translational research. So he really kind of taught me that when you start doing cancer research, you're not ... we have a famous quote from him is that, "The ultimate goal of cancer research is figuring out why people get cancer and how we can treat them better," very loose like that.

That's what he always made us focus. Yes, you can spend many other things doing things, but cancer research at the end, you have to solve problems and apply them and make a difference in a clinic. So those training, both in, Joan's lab and Bert Vogelstein was really influential in terms of setting up my career and doing what I'm doing.

I'm incredibly thankful for the opportunity. I just got a distinguished alumni award from Cornell. This May, which unfortunately we could not celebrate, but I'm just incredibly thankful for the opportunity, to allow me to train here and allowed me to pursue a career and do what I always dreamt like doing. And I think what I see that I see many of the young people now, that we don't want to deprive them of that opportunity.

And I think it's just such a shortsighted, you that I really feel like the problems that affect mankind need to be solved by mankind, meaning like we need to work together, not just as a team in the science, but also as a team, as an international level, and I think it's really just gaining a lot more by working together worldwide, than excluding people from pursuing and contributing to society the best way they can.

Chris Riback: No doubt that is true. And what a terrific story and an acknowledgment of some of those, folks earlier in your career that really opened your eyes to what that feels like. And I can only imagine I'm feeling it in listening to you, what that feels like to have that realization, "Wait a minute, I can have an impact here. I can, I can help human life and help individuals lives."

And it sounds like that was something that, you really came across early through some opportunities in your studies. I just want to make sure to clarify one very important point, which I imagine every listener's going to want to know which is. To be clear, when your mom said, "Kornelia, would you like to go, play tennis this afternoon? Or should we go, would you like to go ski?"

Your response was, "No, mom I'd really like to go dissect something." Am I understanding you correctly?

Dr. Kornelia Polyak: Yes. And I went to summer camps in solving math problems. I know my daughter always thinks that I was crazy, but no, I was like that. I was very much into discovering things and just challenging my mind then solving problems. And I feel like I'm still doing it.
 

Chris Riback: I'm sure that you are, and if your child thinks that you're crazy, then that says to me that only that you're doing, you're doing parenting, right. Because if the children don't think we're crazy, I think we must be doing something wrong.

Dr. Polyak thank you. Thank you for being just a little bit crazy. Thank you for your dedication to science and, to the molecular level, and for the work that you do.

Dr. Kornelia Polyak: Thank you so much. And thanks for listening.

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