Modeling How Cancer Spreads
A New Model Is Helping to Demystify Metastasis
When it comes to treating cancer, early detection is key. But two-thirds of cancer deaths are caused not by the original tumor, but rather by metastasis. Unfortunately, although we know the basics–that cells break away from the original tumor, travel through the blood or lymphatic fluid, and establish new tumors elsewhere in the body–many aspects of the process are still a mystery. As a result, the drugs that have been developed for the purpose of preventing or stopping the process have met with limited success.
A group of researchers from Columbia Engineering have developed a chip that may help scientists to develop an understanding of one of the most mysterious parts of the process of metastasis: why breakaway cancer cells end up where they do.
The Mysteries of Metastasis
Organ colonization by breakaway cancer cells is difficult to observe in humans, and quite difficult to accurately reproduce in animals. There is a shortage of predictive human models, and while animal research has helped scientists to understand a lot about how cancer spreads, it hasn’t allowed scientists to reproduce what happens inside human patients.
This has left us with a number of mysteries.
One mystery is why breakaway cancer cells end up where they do. The process of metastasis isn’t random. Cells don’t simply break away from their tumor and circulate until they find a hospitable place to land. Different types of cancer cells tend to colonize different organs. Breast cancer cells, for example, commonly find a home in the bones and lungs. Testicular cancer cells also metastasize to the bones and lungs, but also often to the brain. Common places for rectal cancers to metastasize include the lungs, peritoneum, and liver.
Nor is the process as simple as the cell planting its metaphorical flag. Once at the new site, cancer cells must attach to the blood vessel lining, cross the barrier, evade local defenses, and then adapt to a new kind of tissue. Only after accomplishing all of this can the invading cells multiply and form a secondary tumor.
But, as we know, cancer cells overcome these obstacles all too often.
“Cancer is very smart, unfortunately,” says the study leader, Columbia Engineering professor Gordana Vunjak-Novakovic.
A New Way to Study the Process
The key motivation for the study, according to Vunjak-Novakovic, has been the pressing need for developing human tissue models of metastasis.
“Our objective was to probe the ability of cancer cells to adhere to and traverse across endothelium [inner lining of blood vessels] and to determine their capacity to survive in the tissues they are colonizing through cell reprogramming and niche remodeling.”
Toward that end, Vunjak-Novakovic’s team at Columbia Engineering have developed a multi-organ chip that recreates one of the most elusive stages of metastasis: the process by which cancer cells cross barriers to get from blood circulation into tissues.
The system follows circulating breast cancer cells as they leave vascular flow and enter engineered human bone and lung tissue. The chip contains separate compartments with millimeter-scale bone and lung tissues connected by a flowing vascular channel. This model is the first of its kind.
The Columbia Engineering team used induced pluripotent stem cells (iPSCs) to produce bone, lung, and vascular endothelium. These stem cells can be guided to develop into different specialized cell types. Tissue-specific scaffolds and bioreactors helped each tissue to mature, while separate compartments provided the necessary conditions for preserving its function over time. The compartments were then linked with vascular circulation.
The flowing channel was separated by a selectively permeable endothelial barrier, mirroring human blood vessel walls. The researchers then introduced breast cancer cells into the circulation, studying them as they encountered the barrier, crossed into nearby tissue, and began to colonize it.
What Researchers Observed
The researchers observed that the behavior of the breast cancer cells mirrored what is already known–that they strongly prefer to colonize bone. And it was in the bone that these cells caused the most damage. Cancer cells with a preference for lung tissue, on the other hand, caused greater damage in the lung tissue while only modestly colonizing the bone.
Researchers were also able to recreate the process by which cancer cells condition the target tissues to make them easier to colonize.
Says Vunjak-Novakovic, “We were also able to reproduce something that happens in patients, where cancer cells condition the target tissues, even before they colonize them, to make them more receptive.”
Before metastatic cells colonize and occupy a distant organ, they release signals that alter that organ’s environment and make it easier to invade. In addition to placing human tissues beside cancer cells, the new model allows researchers to observe the continuous exchange of signals between cells in the bloodstream and the organs they may eventually colonize.
The team believes that recreating this conditioning could help researchers find ways to interrupt metastasis before the cells can establish a secondary tumor.
Patient-Centric Research
Says Vunjak-Novakovic, “The key advantages of this advanced model of metastasis are that it is human and can be patient-specific. It faithfully mimics some of the key aspects of human metastasis that are otherwise largely inaccessible for direct study.”
In addition to using engineered human tissues, the new platform can accept cells from individual patients. This means that scientists can look at individual metastatic behavior as well as metastatic behavior in general. Researchers can alter components of the system one at a time, examine organ-specific interactions, and search for molecular pathways that could become new targets for treatment.
New Directions for Treatment and Research
Columbia’s Laboratory for Stem Cells and Tissue Engineering, which Vunjak-Novakovic also leads, was one of the pioneers of “organs on chips,” that is, small human tissue platforms designed to model disease and drug responses. One of the goals of this technology is to use engineered human tissues to fill research gaps and to help scientists determine which discoveries are most likely to translate to human patients.
Ilaria Baldarassi, a Columbia Engineering PhD student and one of the study’s lead authors, says that the new platform demonstrates how this approach could work in practice.
“As the FDA and NIH place growing emphasis on new approach methodologies, this study is a concrete example of what that shift can look like in practice, applied to one of cancer’s most challenging hallmarks: metastasis,” Baldassarri said.