Perspectives: Mixed Signals
Decoding the trafficking signals that drive neutrophils, for better or worse
Cell migration is essential for development and survival, from the cells of an embryo arranging into tissues and organs, to adult immune cells converging on the site of an infection. But our cells don’t just move randomly. They need signals to tell them when and where to go. And when a tumor gets a hold of these signals, it can use them to recruit immune cells to its team.
Carole Parent, Ph.D., a faculty member at the University of Michigan Life Sciences Institute, explains how her lab investigates the signals that drive immune cells’ migration to infected sites and tumors — and how her approach may translate to new avenues for disease treatment. (Interview edited for length)
What is chemotaxis?
Chemotaxis is the ability of cells to respond to and move toward chemical cues. The process is fundamental in many physiological responses, including development, wound healing and inflammation. When you have a cut on your skin, for example, immune cells are recruited to that area to initiate inflammatory responses, eliminate the bacteria and prevent infection. To find these sites, the immune cells follow chemical signals that are secreted from bacteria and neighboring cells. This process of sensing and migrating toward these signals is chemotaxis.
My lab investigates the mechanisms that regulate chemotaxis by studying the process in immune cells called neutrophils, breast cancer cell lines, Dictyosteliumdiscoideum and mouse models. This combination of simple and complex model systems allows us to dissect the molecular mechanisms of migration under various conditions.
You recently published a study examining how neutrophils, which normally fight disease, might be involved in the progression of triple-negative breast cancer. What did you find?
Coming back to the immune response I just mentioned, neutrophils are key in this response, acting as the first line of defense against pathogens. Interestingly, aside from these established immune defense functions, neutrophils are emerging as one of the key immune cell types that influence cancer progression. Tumors are actually quite heterogeneous. In addition to the cancer cells, many normal cells get recruited to the tumor by chemical cues that are released within the tumor environment.
Given our interest in chemotactic responses, we wanted to answer two main questions in this study: Do breast cancer cells have the innate ability to recruit neutrophils? And if so, do all types of breast cancer cells do this? We found that highly aggressive triple- negative breast cancer cells are actually more effective at recruiting neutrophils than less invasive hormone receptor-positive breast cancer cell lines. The cancer cells secrete the same chemical signals that normally recruit neutrophils, but they also use another signal called TGF-β, which has been shown to promote the generation of “pro-tumor” neutrophils.
In this case, it appears the recruitment of these immune cells to the tumor is actually harmful to patients. Once they get there, the neutrophils activate responses that create an environment where the cancer cells mutate and grow more, and more effectively migrate to reach distant sites. But the role of neutrophils in the context of tumor progression is still a young field compared to other types of immune cells that have been shown to infiltrate tumors. There’s a lot to be discovered.
It sounds like in studying the mechanisms of how the neutrophils get to the tumor, you’re also uncovering more about how the breast cancer cells themselves interact with the neutrophils.
That’s right, and also about how the two cell types form a sort of cross-talk with each other. On one side, the breast cells are secreting components that are going to affect the neutrophils. But once they get there, the neutrophils also alter the properties of breast cancer cells. We want to better understand how all these things work together at a basic biological level.
... that’s really where I want to be: in places where I can interact with people who think differently and can help me think of new ways to explore fundamental scientific questions.
How do the various model systems you use come together to drive these types of discoveries?
We use what I would call a reductionist approach. To avoid the complexity of the tumor microenvironment, for instance, we use a simpler system where we can focus on identifying cancer cell-intrinsic effects on neutrophil function. This allows us to form hypotheses that we can test in more complex model organisms. Indeed, in more complex systems, like a mouse, it becomes difficult to tease apart the very fundamental mechanisms because so many things are changing at the same time.
Another example of this approach is our research into how neutrophils reach sites of inflammation. We began with isolated neutrophils, where we could control the immune cell environment. We identified a small lipid mediator that is essential for recruiting of neutrophils to these sites, and then we used mouse models to confirm that the lipid mediator is also required in animal systems. But to identify the mechanisms that regulate the release of the lipid mediator, we had to go back to working with the neutrophils. This led us to uncover potential therapeutic avenues for treating chronic inflammatory disease, where the presence of neutrophils becomes harmful.
In addition to investigating multiple model organisms, you’ve also collaborated with researchers across fairly divergent life sciences fields. What led you to develop this transdisciplinary approach, and what impact has it had on your discoveries?
For me, a multidisciplinary approach is key to my research program. Before I came to U-M, I was at the National Cancer Institute, where I helped establish a collaborative environment between cancer biologists and physicists. That experience exposed me to people who think differently than me and helped me think outside of my box even more. It led me to go much deeper into questions in ways that I really hadn’t thought about before.
The LSI was a perfect next step for me, because the institute houses investigators from different fields, working together and helping each other grow scientifically. And that’s really where I want to be: in places where I can interact with people who think differently and can help me think of new ways to explore fundamental scientific questions
What is next for your lab at the LSI?
Every day provides a new “next” or new opportunity for discovery. We are often faced with unexpected results that open new questions to explore. Right now, I’m looking forward to expanding our work with animal models through collaborations, so we can continue to apply our basic science knowledge to systems that are more relevant for translational research.