The Microenvironmentalist
Ashani Weeraratna’s groundbreaking research looks beyond tumor cells to understand the role of aging in cancer.
For new Bloomberg Distinguished Professor Ashani “Ashi” Weeraratna, context always matters—whether at the molecular level or the institutional. As a cancer researcher, Weeraratna, PhD, studies microenvironments—the cells and structures around tumors that either spur their growth and metastasis or hold them in check. As the inaugural E.V. McCollum Chair and Professor in Biochemistry and Molecular Biology, she plans to build a community that allows top-notch researchers and research to thrive.
She comes to the School well-equipped for the task. After an oncology postdoc at the Johns Hopkins School of Medicine, she conducted melanoma research at the NIH and then joined the Wistar Institute, where she co-led its Immunology, Microenvironment, and Metastasis program.
In this Q&A, she discusses the power of microenvironments to shape the trajectories of tumors—and entire careers.
You’ve spent most of your career studying the role of Wnt5A in cancer. How did you come to focus on that gene in particular?
When I got to Jeff Trent’s lab [at NIH], they were really into genomics and genetics. Jeff had just done this big microarray on melanoma and which cells are likely to metastasize and which are not. Wnt5A was the number one gene that identified metastatic cells from non-meta-static cells.
Jeff said, “I hired you because you’re a cell biologist. You go figure out what this gene does.” So that’s what we did.
Were you interested in melanoma research before you went to that lab?
No, I came from a prostate cancer lab here at Hopkins (John Isaacs’ lab). I wanted to do microarrays on prostate cancers, but Jeff said, “You can do that later. First we need to work on this project.” And then that became so interesting that I never really went back.
In addition to that, the melanoma field in general was so embracing. They brought in young investigators to their annual meeting, and still do to this day. It didn’t matter if you’re a man or a woman or a person of color. It was just this really diverse group of international and domestic researchers, basic and clinical scientists. It was such an engaging community that I just stayed. I love it.
That says a lot about the importance of community and culture at a research institution.
I’m a big believer in microenvironments.
Let’s talk about them. When people think about cancer, microenvironments aren’t the first thing that springs to mind. The immediate thought is—
—what’s happening in the tumor cell. Well, that’s how I started out.
But after I left Jeff’s lab, I went to the National Institute on Aging. I couldn’t help but hear [other researchers talking] about all these changes that were going on systemically with aging—your knees get worse, or your brain changes, or the inflammation in your body changes. That led me to start thinking about the fact that the incidence of most cancers skyrockets after age 55.
We became really interested in what was happening around those tumor cells. Because I work on melanoma, which is a disease of the skin, we took skin fibroblasts from normal healthy donors in their 20s and their 50s and asked, What are the changes going on, and how will those changes affect tumor cells?
That led to what has been the last almost-decade of work in my lab: trying to understand these age-related changes at a molecular level and how those drive tumor cells to behave aggressively.
Melanoma patients in their 40s may have tumors excised very early, and then they may not come back for 10 or 15 years. But they almost always recur. What is changing as that organism ages 15 years, and how does that wake tumors up?
What kinds of things happen?
One thing that happens that we all hate and can’t get away from is wrinkling. You have collagen and elastin, which are bound together, very tightly cross-linked. When you’re young, the skin is very smooth across the top because it’s got this firm structure beneath it. As you age, however, those cross-links break apart and the skin starts to fold in. And that’s what wrinkles are.
Our lab asked, With that matrix breaking down, does that allow melanoma tumor cells to grow better, move better? And we found that that was the case.
You studied an immunotherapy drug that was more effective in older patients than younger patients. That seems counterintuitive, given all the problems that come with aging.
Yes, that surprised us.
We discovered that younger immune systems have more checks and balances—and express more regulatory cells that interfered with the immunotherapy. It was super exciting because it tells us that one drug doesn’t fit all. In cancer research today, we’re all designing therapies and using them to treat all patients. These data suggest that maybe it’s better to treat older patients with one kind of immunotherapy and younger patients with a targeted therapy or other immunotherapies.
In that study, once we figured out a specific type of regulatory cell was the problem, we targeted it before we gave young patients immunotherapy. Then they responded as well as the older patients.
Has that translated into recommendations for this medication?
Not yet. Those things take a long time.
Well, basic science moves methodically—
And glacially.
But you’ve seen some big changes already in your career.
Oh, absolutely. I would say that 15 years ago, if a patient walked into the clinic and had stage 4 melanoma, they’d say, “You will need to get your affairs in order.” But now 30% of those people will actually be disease-free 10 years later. Some of the new immunotherapies have a lot to do with that.
What are the next big questions that you really want to answer?
I’m excited about understanding tumor dormancy. Melanoma patients in their 40s may have tumors excised very early, and then they may not come back for 10 or 15 years. But they almost always recur.
The question is, What is changing as that organism ages 15 years, and how does that wake tumors up?