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Breast Matters - A Conversation with Cell Biologist Andy Ewald

Breast Matters - Fall 2014
Issue No. 5

A Conversation with Cell Biologist Andy Ewald

Date: December 15, 2014

About the Spread of Cancer Cells and How to Stop It

Normal breast ducts are composed of two layers of cells, luminal epithelial cells that make milk (light gray) and myoepithelial cells that push the milk out of the ducts during nursing (brown cells). Breast cancer typically arises when luminal epithelial cells begin multiplying out of control (blue cells).  As long as these cancer cells remain within a protein barrier, referred to as the basement membrane (red), they can’t spread beyond the breast.  The Ewald Lab recently discovered a conserved set of genes that are expressed in breast cancer cells that can invade past the basement membrane and spread to distant organs (green/blue cells).

Watch Dr. Ewald’s Science: Out of the Box video “Breast Cancer Breakthrough:  Stopping Leader Cells” on the Johns Hopkins Medicine You Tube channel.

Johns Hopkins cell biologist Andy Ewald is a master at explaining his super-sophisticated cancer research in super-simple terms. Take, for example, a recent Youtube video, part of the Johns Hopkins Medicine video series called Science: Out of the Box. Ewald uses three different colored blobs of Play Doh and a handful of colorful beads to describe a recent breakthrough discovery by his team at the Center for Cell Dynamics. He uses these colorful manipulatives to explain—in terms everyone can understand—how he and his team have identified a leader cell, a specific type of cell that aids in the spread of breast tumors.

Ewald’s mastery at breaking down complex subject matter for public consumption isn’t the only thing that comes across clearly in the video, so too does his intensity of purpose. It’s no wonder, given that much of Ewald’s research hinges on questions that, if answered, could result in life-changing consequences for countless patients with breast cancer. Recently, Ewald took a break from his work in the laboratory to share some information about his exciting research projects—in layman’s terms.

What is your primary research objective as a cell biologist?

Most broadly, my lab is focused on understanding metastasis in breast cancer: how cells spread to distant organs, and which genes are required for that process.

You recently identified a class of breast cancer cells that leads the process of invasion into surrounding tissues. Talk about this research and its significance.

We first studied tumors from mice. We then developed a technique to take tumor tissue from patients and ask the same question: How does a primary breast tumor invade? By looking at a tumor, direct from surgery, using 3-D culture techniques, we saw that a specialized population of cancer cells—leader cells—were the most important to the process.

What was unique about these particular cancer cells?

We found that a protein, cytokeratin 14, or K14, was present in almost all leader cells but very rarely in the noninvasive parts of the tumor. We then looked at mice with other types of breast cancer. All had leader cells containing K14. The more invasive the tumor, the more cells with K14.

You also have discovered that the makeup of cancer cells is not the only factor responsible for the spread of cancer; the environment surrounding the cancer cells also may play a role. Talk about that.

We knew the environment around the breast cancer tumor was changing dramatically at the same time that the cells were migrating. So we wanted to test the importance of these changes in the “protein scaffolding” that surrounds the tumor. To accomplish this goal, we took pieces of the same primary (human) breast cancer tumor and randomly allocated them to two different environments within 3-D gels: one that mimics the microenvironment surrounding healthy mammary tissue and another that mimics tumorous mammary tissue.

What happened next?

We observed that almost all of the tumor fragments sent cells crawling into the tumorous microenvironment. Almost none of the tumor fragments sent cells crawling into the normal, non-tumorous microenvironment. Our experiments revealed that the ability of the tumor to spread is dependent on the composition of the protein scaffold surrounding it.

Do you plan to take a closer look at the ‘protein scaffolding’ that allows cancer cells to bypass this boundary and begin migrating to another part of the body? 

Yes. We now know that for tumor cells to spread, they need to interact with proteins outside the tumor. We also know that a gene, called Twist1, is overexpressed in some types of breast cancer and is associated with metastasis in mouse models. In a recent study, we observed an interesting interaction between Twist1 and E-cadherin. E-cadherin is sometimes called the Velcro protein, because it helps bind together epithelial cells, which give rise to about 85 percent of all cancers.

What happened in the interaction between Twist 1 and the Velcro protein?

We turned on Twist1 in epithelial cells that lacked the Velcro protein, which helps bind the cells together. The cells were no longer able to escape into the gel, as they did when we turned on Twist1 in epithelial cells that contained the Velcro protein. This observation caused us to rethink the role of E-cadherin in metastasis. We discovered that it isn’t just sticking cells together; it is also an important part of the protein machinery that enables the detachment and migration of single cells from the tissue.

It sounds like you’ve made some incredible headway in understanding how breast cancer spreads. What’s next?

Going forward, there is an urgent need for therapies that target the spread of breast cancer. We’d like to turn it into a chronic, managed disease. We’re optimistic because, for the first time, we have assays that allow us to study the rise and spread of cancer cells right before our eyes. We’re finding out a lot of new and surprising things about the molecular biology of breast cancer. Before, we didn’t have good assays to study the systemic spread of the disease. We’re now working with engineers, oncologists, pathologists, and others to understand how we can take our laboratory insights and develop new therapies for patients with breast cancer. We’re working as hard as we can because we know how many people are depending on us.