View metadata, citation and similar papers at core.ac.uk brought to you by CORE People & Ideas provided by PubMed Central Michael Overholtzer: Answering existential questions on entosis Overholtzer is working to understand how and why tumor cells invade one another. hen a pair of tumor cells break you have to market it in order to keep go- free of their attachments to ing. You even have to keep inventory. You W the extracellular matrix, some- have to be on top of everything. thing very strange can happen. One cell can dive into its neighbor, becoming com- Have you always known you wanted to pletely enveloped and usually dying as a be a scientist? result. These cell-in-cell structures are Actually, I was interested in biology when frequently observed in advanced, aggres- I was in high school, but I chose to go to sive cancers, but, until Michael Over- Ithaca College largely on the basis of its holtzer came along, they had not been strong music program. I loved classical studied in any detail. music, mainly violin and voice, and knew Overholtzer began studying cancer biol- I wanted to study it. I ended up minoring ogy as a graduate student with Arnold in voice. But I didn’t really have any sort OF MEMORIAL SEPTIMUS, COURTESY PHOTO BY MATTHEW SLOAN-KETTERING CANCER CENTER Levine at Princeton University (1). But he of career plan at that time. Michael Overholtzer fi rst encountered this process, which he Ironically, I think part of the reason I would later name “entosis,” while he was a became a scientist is that Ithaca College postdoctoral researcher in Joan Brugge’s doesn’t have a graduate program for the When it came to my own graduate re- lab at Harvard (2, 3). It immediately en- sciences, so the only research there is done search project, though, I would say I devel- thralled him: Why would a cell choose to by undergrads. That gave me the oppor- oped it by trial and error. [Laughs] Most of invade another cell like this? What biologi- tunity to link up with a lab and start doing the time our interesting ideas didn’t work cal purpose does it serve? And how does it research. I was also lucky to fi nd a great out. I failed at a lot of projects, but that expe- happen? These questions are now the focus mentor who gave me the freedom, even at rience was great for my professional devel- of his own lab (4, 5), which he started in that young age, to feel like I could discover opment. Failure is a huge part of discovery. 2008 at the Memorial Sloan-Kettering something. I had a real sense that what I Cancer Center in New York. We called him was doing was important, and I realized Why did you join Joan Brugge’s lab for to ask what answers he currently has to that I love being an experimentalist. your postdoc? these questions and what he’s By the time I had fi nished my PhD, I had looking into next. Do you still sing? met my future wife. I wasn’t even sure “That’s the With a voice minor, it was whether I wanted to do a postdoc, but I OPEN FOR BUSINESS $64,000 kind of inevitable that I end- talked it over with her and we decided I Did you have any role ed up getting into rock bands. would give it two years and see how things models when you were question: Why I still have friends who play worked out. When I started looking for growing up? would a cell in this or that band, mostly as postdoctoral opportunities, I was already I think it’s interesting that do this?” a hobby, but I haven’t been familiar with Joan’s work—really cool and both my sister and I ended doing much of that lately. I imaginative work modeling breast cancers up getting PhDs. I think that have three small kids, and, using 3D culture. So I interviewed with probably has something to do with the together with starting my own lab, that her, and her lab was a perfect fi t for me. way we were raised by my parents. They hasn’t left me much time for hobbies. But once again, I had multiple projects in did a good job of bringing out their chil- Joan’s lab, and most of them failed. I kept at dren’s curiosity. OPEN-MINDED it for more than two years, though, because I was also close to both sets of my Did you have any plans for what to focus by that point I couldn’t imagine wanting to grandparents, but in particular my father’s on in your graduate work at Princeton? do anything besides research. At the time we father, who ran a small business called When I arrived at Princeton I had a very made the observations that formed the basis Overholtzer’s Radio and TV Service. I open mind, and I could probably have end- for what my own lab is now working on, I think about him a lot these days because, ed up working on anything. But I happened had two or three projects that were in various now that I’ve had my own lab for three to really enjoy my lab rotation with Arnold states of working, or not. But then I noticed years, I’ve started noticing how running a Levine because everyone in the lab had a something that just blew my mind: I would lab is a lot like running a small business. different project and because they were all sometimes see one cancer cell become com- You have to hire and manage employees, trying to ask exciting, big questions. And pletely engulfed by another. Neither Joan you have a product that you make, and Arnold was a great mentor for me. nor I had any idea what to make of it. 924 JCB • VOLUME 195 • NUMBER 6 • 2011 Text and Interview by Caitlin Sedwick [email protected] Our fi rst thought was that we had stum- undergo something resembling an invasion bled upon the mammalian equivalent of of the enclosing cell. But the enclosing cell something that happens in C. elegans, where probably also participates in the process, in sometimes one cell eats a neighboring cell ways that we just haven’t uncovered yet. that’s about to undergo apoptosis, and the The simplest way to think about it is engulfi ng cell plays a role in killing off the that the cells are initially connected by a dying cell. So I set about trying to trigger normal epithelial junction. But if the cells IMAGE COURTESY OF OLIVER FLOREY IMAGE COURTESY this process—which we later called entosis aren’t adherent to some surface, they don’t An entotic cell is contained within a large after the Greek word for “inside”—using have any way to counter the contractile vacuole inside its host cell. every approach I could think of, but nothing forces they are exerting against each other. worked until I realized that I had been trying So if one cell is contracting more than the all my treatments on adherent cells. In fact, other, it just keeps pulling the junction promotes tumorigenesis. My instinct is that entosis only happens amongst cells that are around itself until it becomes engulfed. entosis’ overall impact on tumor growth is detached from their substrate. situational; it’ll depend on the context of the OPEN QUESTION tumor or the timing of the event. When did you recognize the potential What purpose does entosis serve? signifi cance of your observation? That’s the $64,000 question: Where do you go now? Not until I’d been working on it for some Why would a cell do this? We “As we tackle Overall, we’re looking at en- time and happened to show my data to a don’t know the answer yet. tosis on two levels: One, what pathologist, who said, “You know, you From what we know today, the biology can entosis teach us about can see this in cancer. It’s not hard to the cell that goes in seems to of entosis, basic biology? What basic pro- fi nd.” Pathologists had noticed it a long be an active participant, but we’re always cesses are at work here, and time ago, and they call it a “cell-in-cell it’s unclear whether it could what triggers them? Our re- structure.” We’d had no idea! You can’t do get any benefi t from doing keeping an cent paper on the role of auto- a PubMed search on something if you this. It may be a suicide eye out for phagy on entotic cell death is don’t know what search term to use. method, because most of ways to turn a good example of that ap- these cells will die. However, proach, and half my lab is Point of grammar: Is entosis done by the engulfment is not suffi cient it on or off.” following up that fi nding by engulfi ng cell or the one being engulfed? to trigger death. Instead, the looking at what triggers this I think the word entosis really just refers to internalized cells have to be executed by death pathway. The other half is working on the engulfment mechanism that occurs be- their hosts, or else they can escape. In fact, questions related to cell–cell adhesion: How tween pairs of cells.