Growing up, everybody had that one friend – that guy or gal with bad ideas and a knack for getting you to play along. And the thing is, that darn friend never got caught! Somehow, when the jig was up, your friend was nowhere to be found and there you were left holding the bag.
University of Colorado Cancer Center Associate Director and the Margaret Turley Grohne Chair for Basic Research, Heide Ford, PhD, thinks it might be the same with breast cancer. In breast cancer, you’ve got “Wally” cancer cells and “Eddie Haskell” cancer cells – Ford’s work shows that these “Eddie Haskell” cancer cells may talk “Wally” cells into the bad idea of metastasizing, giving them the skills and the push they need to travel through the body to seed new tumors. Now, an R01 grant from the National Institutes of Health totaling $3M over five years may help the Ford lab and the Lewis lab from Baylor University mute the conversation between Wally and Eddie Haskell, keeping Wally cells at home in the primary tumor where they are much less dangerous.
Of course, the Ford lab uses other words to describe these players and processes.
Technically, the “Wally” cells are cancerous epithelial cells that make up the bulk of a primary breast tumor. And “Eddie Haskell” cells are ones that have undergone something called an epithelial-to-mesenchymal transition (EMT). Alone, epithelial cells normally don’t leave the primary tumor. But mesenchymal cells can and do. Only, when researchers study breast cancer metastases, they find these new tumors at secondary sites are composed of epithelial and not mesenchymal cells. If epithelial cells can’t travel, where did they come from? And if mesenchymal cells are the dangerous ones, where did they go?
The prevailing view has been that epithelial cells undergo EMT to become mesenchymal cells, which travel through the body, and then once they find an appropriate site for metastasis, they transition back to epithelial cells, undergoing the reverse transformation called MET.
“But what if that assessment isn’t always correct?” Ford says. “Maybe the cell that undergoes the EMT is not the one that is able to grow at the metastatic site? What if some cells undergo EMT and then talk to epithelial cells to make them more metastatic? What if these EMT cells are somehow changing the properties of the epithelial tumor cells?”
There is growing support for this idea. For example, researchers have used a technique called fate mapping to label and then track individual cells. Using this technique, they can see in their models, that cells that have undergone EMT do not, in fact, become part of the new tumor – it’s not that an individual cell undergoes EMT, travels, attaches, and then undergoes MET.
“Is EMT required for metastasis? Some think yes and some think no. We provide another option, namely that EMT is required, but not, perhaps, due to EMT cells themselves growing out at the secondary site, but rather to their ability to talk other cells into metastasizing,” Ford says.
In fact, previous work in the Ford lab has shown the pathway required for this “crosstalk” between EMT and epithelial cells. The hedgehog signaling pathway is implicated in many cancers including breast cancer, and, in fact, hedgehog inhibitors have already been tested in clinical trials. However, despite their promise, hedgehog inhibitors have been largely unsuccessful.
According to Ford, the problem may be that, “Drugs can inhibit this pathway, but only upstream – it may be that these drugs are not working because they’re not hitting downstream enough.”
Think of interrupting the hedgehog signaling pathway like blocking the flow of a river before it reaches a small town. Existing hedgehog inhibitors block the water far upstream, and yet somehow water finds its way around the blockade and the town is still flooded. Ford hopes that by blocking the water further downstream, or perhaps somewhere in between, she could keep the town dry. One candidate is blocking the flow of water through the hedgehog pathway at the point of a gene called Six1. Signals from Six1 activate hedgehog signals in neighboring cells, and the Ford lab has been deeply involved in the development of novel inhibitors of Six1, with the intention of damming the flow of information at this point. Other options for inhibiting hedgehog signaling also exist and will be tested as part of the current grant.
“Basically, we hope to use patient-derived tumor models to run a whole bunch of pre-clinical trials. We’re going to use these models to test novel therapies to inhibit crosstalk and stop metastasis,” Ford says.
Breast cancer only kills once it spreads to other areas of the body, like bone, brain, liver or lung. Now with National Institute of Health support, Ford hopes to contain breast and potentially other cancers as well.