Mikala Egeblad wants to put the brakes on cancer progression

Internationally recognized cancer researcher Mikala Egeblad describes much of her career as driven by the idea that how the body responds to cancer determines how aggressive the cancer becomes. Fueled by a desire to help cancer patients mitigate their risk of recurrence and metastasis, as well as a pure fascination with observing cells under a microscope, Egeblad has devoted her career to investigating how the tumor microenvironment—the immune cells, blood vessels, chemical signals, and support matrix surrounding a tumor—regulates cancer progression.

"Broadly speaking, I study how the body interacts with cancer cells," Egeblad says. "We can do this on different levels. At the microscopic level, we can observe in real time how the body's cells respond to cancer. On a macro level, I'm interested in hormones secreted in parts of the body working as signals to other parts of the body to elicit stress hormones. Going even beyond that, I investigate how external stimuli affect cancer progression."

Egeblad joins Johns Hopkins University as a Bloomberg Distinguished Professor of Tumor Microenvironment with appointments in the Department of Cell Biology and the Department of Oncology in the School of Medicine. She will co-direct the Cancer Invasion Metastasis Program in the Sidney Kimmel Comprehensive Cancer Center and act as associate director of the Giovanis Institute for Translational Cell Biology. She will also be a member of the Convergence Institute, which aims to accelerate progress in the fight against cancer by building, training, and catalyzing convergence teams that will utilize their diverse scientific disciplines and technologies to foster innovation.

Egeblad's work has greatly contributed to the understanding of how the tumor microenvironment regulates cancer disease initiation, progression, and metastasis. Communication between the tumor and its microenvironment influences the tumor's growth, response to therapy, and ability to metastasize, or spread to a different part of the body than where it started. While most microenvironments help tumors grow and metastasize, some can restrict tumors. Egeblad investigates how to target the bad microenvironments and support the good ones to prevent metastatic spread.

"My ultimate goal for my research is to prevent metastasis from occurring, and to develop better therapies to more effectively fight cancer," Egeblad says. "Once a patient has had cancer, even if the tumor hasn't spread, they never really know whether or not the cancer will come back. We don't yet understand who will be the lucky ones for whom cancer never reoccurs, or why cancer sometimes comes back after extended dormant periods and metastasizes."

Egeblad examines the functions of immune cells known as myeloid cells, a type of blood cell that originates in the bone marrow. She studies how different types of myeloid cells are recruited to tumors, and how signals between the myeloid cells and cancer cells or other immune cells influence cancer progression, including metastasis, as well as response to chemotherapy.

"A lot of what we've looked at has been what type of signals accelerate metastatic spread," Egeblad explains. "This includes cancer that has already spread, but may not be very dangerous because it is not growing. From those studies, we're starting to build ideas on how to devise therapies that can help the body contain the spread of these cancer cells."

Egeblad is a technical pioneer in modeling, imaging, and real-time analysis of cancer processes. She co-developed intravital microscopy, a form of microscopy that involves the surgical implantation of an imaging window into animal tissue, allowing for the real-time observation of living cells in their natural environment within living organisms at high enough resolution to distinguish between individual cells. In addition to her own use to study interactions between the tumor microenvironment and cancer cells in living mice to determine what influences cancer cell survival, proliferation, and migration, intravital microscopy is now widely used in a range of research areas, particularly to study disease progression and drug efficacy.

Egeblad says her love for imaging and observing cells is a large part of what brought her into this career path, and what has enabled her to forge new research paths and discover important cancer mechanisms that were previously overlooked.

"It's just incredibly exciting to see how cells interact, how they move, how immune cells kill cancer cells," Egeblad says. "A lot of my career has been guided by kind of serendipitous directions where I find something unexpected that piques my interest, and then I tend to follow that lead. I don't think I will ever get tired of looking at cells under a microscope."

Egeblad has been instrumental in establishing interest in as well as illuminating the role of a specific type of myeloid cell called a neutrophil in cancer progression and metastasis. Neutrophils form an essential part of the immune system, protecting the body against disease. Neutrophils release neutrophil extracellular traps, web-like networks of fibers consisting mostly of DNA and proteins that play a key role in the body's innate immune response by trapping and containing invading pathogens. However, when not properly regulated, neutrophil extracellular traps can also cause inflammation.

Until recently, little attention had been paid to neutrophils and their functions in cancer. Egeblad has been a driving force in identifying the mechanisms by which neutrophils influence cancer progression, and specifically how neutrophil extracellular traps can promote metastasis. She has written multiple landmark reviews to advance the field and to establish a framework for understanding how the microenvironment around the cancer cell impacts tumor function. Her lab has shown that activation of neutrophils during inflammation can cause cancer to recur by forming neutrophil extracellular traps, which alter the matrix surrounding the dormant cancer cells to provide a wake-up signal. Yet, in some cases, neutrophils can also kill cancer cells, although the conditions under which this occurs are still poorly understood. This line of Egeblad's work has opened up new avenues for activating the immune system to attack metastatic cancer and holds promise for potential future treatment options.

"Early in my career, I was really focused on all the bad players, and how the cancer cells would reinstruct the host so that the body would help the tumor grow faster, become resistant to therapy, and therefore become more aggressive and spread throughout the body," Egeblad says. "However, there are also ways that the body helps overcome that through the immune response—that's one way of awakening the 'good' microenvironment. I am now interested in investigating ways to reprogram the host response in order to fight the cancer and ultimately go back to a good microenvironment."

Egeblad comes to JHU from the Cold Spring Harbor Laboratory, where she was a professor and Cancer Center program co-leader. She earned her BS in Medicine, her MSc in Human Biology, and her PhD in Cancer Biology from the University of Copenhagen. She completed a postdoctoral fellowship at the University of California, San Francisco, before joining the faculty at UCSF.

"I'm excited to welcome Dr. Egeblad to Johns Hopkins," says Theodore DeWeese, interim dean of the School of Medicine. "Her work with myeloid-derived immune cells has advanced our understanding of the genesis and treatment of some of the most pernicious cancers we encounter. Her research into the microenvironments of tumors showed us that, when we alter certain conditions, cancer therapy can be even more effective. I so look forward to seeing what Dr. Egeblad does at Johns Hopkins."

At Johns Hopkins, Egeblad is excited to expand a major new direction of her interdisciplinary research, and further grow her collaborations with neuroscientists to learn more about how the brain regulates the immune system to combat cancer. Specifically, she is interested in how the brain senses stress and, as a result, promotes the spread of cancer, and what could be done to stop this. Egeblad is optimistic that her proximity to the clinic as well as the many opportunities for interdisciplinary work and collaborations at JHU will open up new research channels.

"Coming to Johns Hopkins will challenge me to think in new and different ways," Egeblad says. "A lot of what I do is translational, on the border between the medical field and basic cell biology. I always strive to incorporate whatever is helpful for moving the research forward, and challenge myself to think about how different projects are interrelated, and how we might make connections that may not seem obvious.

"For a long time, I have wanted to bring my research closer to the clinic—both in terms of the research questions I focus on as well as evaluating if any of our discoveries can be used to identify patients at risk for metastasis or ultimately develop new drugs and therapies to combat cancer. My work will benefit from the incredibly diverse community of scientists across the university. In addition, the established community of cancer immunologists at Johns Hopkins and the seminal work that has been done here on immunotherapies is really inspiring to me, and I'm really excited to come work alongside and with the people that have brought about many of these incredible achievements."

Says Stephen Gange, interim provost at Johns Hopkins University: "Mikala Egeblad's innovative research brings together techniques from a wide range of disciplines in novel ways to advance our understanding of cancer disease progression. Her technical and conceptual strengths will accelerate cancer research efforts at Johns Hopkins, and I expect she will quickly become an integral part of our research community."

As a Bloomberg Distinguished Professor, Egeblad joins an interdisciplinary cohort of scholars working to address major world problems and teach the next generation. The program is backed by a gift from Michael R. Bloomberg, a Johns Hopkins alumnus, founder of Bloomberg LP and Bloomberg Philanthropies, World Health Organization Global Ambassador for Noncommunicable Diseases, United Nations Secretary-General's Special Envoy for Climate Ambition and Solutions and 108th mayor of New York City.