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Intravital Imaging Offers View of Cancer Cell Interaction With Immune Response

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000529893.71988.32
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Far from her native Copenhagen, Denmark, Mikala Egeblad, PhD, works tirelessly to find a means to reduce cancer metastases and recurrences. The significance of her work, now centered in her lab at Cold Spring Harbor Laboratory, Long Island, N.Y., where she is an Associate Professor, has resulted in the Department of Defense Breast Cancer Research Program Era of Hope Scholar Award in 2014 and a Pershing Square Sohn Prize for Young Investigators in Cancer Research in 2017.

“Tirelessly” is not an exaggerative adverb in Egeblad's world. “Sometimes I just wish I had more time to devote to my work. I don't need strategies for diffusing the tension of research because I really do love it,” she proclaimed, noting that spare time is happily spent with her partner, their two young daughters, and sometimes an ice cream maker.

“I like to make ice cream—walnut ice cream,” she said, though she defaults to berry flavors for the children. “When I was still in Denmark, I used to play the oboe and flute for relaxation, but there is no time for that now. Ice cream, however, is always there when you need it,” she added with a chuckle.

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Finding Her Path

In her youth, Egeblad loved mathematics, but followed in the footsteps of her parents—both physicians—when she opted to begin medical school. “We go directly from high school to medical school in Europe,” she explained, adding that it was a last-minute decision because her career path was not yet clear to her.

In her third semester, she took a class in molecular and cell biology, and “... fell in love with that area of science. I remember how I loved that textbook; I read it very carefully,” she recalled. “I approached one of my professors to ask if I could volunteer in his lab.” When fellow med students happened to comment to her that they had never seen her as happy as she was when in the lab, the die was cast.

“That comment made me think and actually convinced me to switch from medical school to a research program in human biology. My focus was no longer to be a physician, but to be a researcher,” Egeblad recalled. “I enjoyed being in the lab, designing experiments around ideas and seeing what the results would be. I found all of that very satisfying.”

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Forging New Possibilities

After receiving a PhD at the University of Copenhagen, Egeblad travelled to the University of California, San Francisco to do postdoctoral research in the area of tumor microenvironment with one of the leading voices in that field, Zena Werb, PhD.

“That was a fantastic time because Dr. Zerb offered an environment where we were encouraged to think big, to ask ourselves how we could go in completely new directions,” recalled Egeblad. “She provided both the intellectual and the financial support to do things that were very different. With her, I was able to develop intravital imaging (imaging in live mice). While other people developed similar methods at that time, I developed the method we still use in my lab today.

“The technique is important because it allows researchers to see in real-time—or, more accurately, 900 times the speed of real-time—what is going on inside a tumor while it is in an organism and living. It allows us to see how cancer cells respond to drugs, how immune cells interact with the cancer cells, how the cells divide, how they die, how they metastasize. We watch these processes as they occur,” explained Egeblad.

Today such images are created in Egeblad's lab using a spinning disk confocal microscope. “We use mice where we have manipulated different cells so they have fluorescence and different colors. Blue cancer cells, for example, turn red when they are dying. We can have immune cells appear in green, the blood vessels in yellow, enzymatic activities in purple, and so on. All these colors let us see where and how all these different elements affect each other. We take pictures over time—every minute or every 5 minutes—and splice them together to make a movie of what is going on.”

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Related Discoveries

Egeblad said major occurrences have been discovered. “First, we saw how cancer cells respond to drugs in real-time. The striking thing was that, while the cancer cells respond, there was also this immune (inflammatory) response to dying cancer cells,” she explained, clarifying that inflammatory cells are immune cells and part of the innate immune system (as opposed to T cells, for example, which are adaptive immune cells).

“The fact that inflammatory cells were coming into the tumors after the cell death had occurred lead us to question whether this inflammatory response is a good thing or a bad thing—and we learned it was a bad thing. We found these new cells, coming into the tumor that is being treated, bring in factors that actually help the cancer cells survive and grow again after treatment.”

Egeblad said she can characterize this unexpected turn of events by using a Star Wars reference. “It is as if these immune cells are turning to the Dark Side,” she commented. “These cells that are there to combat pathogens and clean up wounds, when in contact with cancer, can actually end up making the tumor grow faster and metastasize.”

Phase I clinical trials are now being conducted by drug companies to see if there is a therapeutic means to inhibit these offending inflammatory responses. “We are awaiting results to see how it works. Some drugs look promising, but they need to get to the big phase III studies for us to know if they truly work,” noted Egeblad.

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Neutrophil NETs

Another important area of Egeblad's research arose from imaging in lungs to see how cells establish a metastasis. “Quite surprisingly, we discovered that immune cells called neutrophils can re-activate dormant cancer by forming so-called neutrophil extracellular traps (NETs). Normally, NETs kill bacteria. Neutrophils form NETs by expelling their DNA, which is sticky and traps the bacteria. Bound to the NET-DNA are enzymes that can kill bacteria, but these enzymes can also lead to tissue degradation. And that tissue degradation makes it easier for cancer cells to get into the lungs, start dividing, and form a metastases. In short, this ‘re-awakens’ the cancer cells.”

Egeblad said an important job now at hand is to develop strategies to prevent neutrophils from forming NETs or to overcome and tame the NET structures damaging the tissue. “We are trying, in our mouse models, to determine the best approach to prevent metastasis caused by activation of these NETs,” Egeblad explained. “In addition, we are trying to explore the bigger questions: Why do some people get metastases while others do not? Does that have anything to do with whether they have activation of these neutrophil NET structures? We know they can be activated by the cancer cells themselves, but not all cancer cells do it.

“We have looked at different types of breast cancer and have found that the most aggressive types of cancer cells can activate the neutrophil to form NETs. We also know that some bacterial infections activate these structures,” she continued. “So one thing we are exploring right now is if patients have an infection, does that affect their risk of metastasis? Some early data suggests that, yes, it is the case. We also suspect that yeast infections might do this, but as yet we do not know with certainty.”

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New Strategies Emerge

When asked if she feels she is truly on the verge of a new and original way to strike at cancer, Egeblad did not hesitate. “Yes, I do. But obviously we would like to see results from human studies, too. While we have come very far at looking at this in mice, we have just done a little bit of human analysis in breast tumors to see if we can find these structures—and we can in the most aggressive tumors, but not in the least aggressive ones. We don't know yet how important this is in humans and if this knowledge can be used to prevent human cancer metastases. We do think [formation of NETs] is at least part of the equation when identifying aggressive cancers. But I would stress that there are many ways one can form a metastasis, so this may be just one that we can monitor and prevent.”

More fully understanding how NETs work is paramount among Egeblad's short-term goals. “Once we know exactly how they work and how they promote metastasis, we can target them more efficiently. We will be able to take our discoveries into more clinical-oriented studies to see if we can reduce risk of metastatic recurrence,” she said.

As for the ultimate payoff of her longer-term lifetime work, Egeblad said she and other researchers must aim at cancer cures. “I hope to see many more patients who are actually cured of cancer. We have things—CAR T-cell therapy, checkpoint blockades, for example—that appear to have cured some cancer patients. That has changed the mood among all cancer researchers. A few years ago, the best we could offer someone was a chronic disease. One didn't even think a cure would be possible. Now we know it might be. In terms of my own research, the specific goal is to get to the point where, after people come in and have a primary tumor removed or treated, we will successfully prevent it from coming back.” It's a lofty goal, admitted Egeblad. “But if we shoot for the moon, at the very least we can get out to the space station.”

Just as her mentor, Werb, encouraged Egeblad to think outside the box, Egeblad urges others to look beyond tumors for insights. “Looking at these inflammatory cells is teaching us that they are an important additional target,” she stressed. “It simply is not sufficient to look only at cancer cells. Looking at tumors in living mice and learning how cancer cells react to inflammatory cells has given us important new insights into disease. We must stay on the path of discovery and progress.”

Valerie Neff Newitt is a contributing writer.

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