This is an artist's depiction of the dangers of metastasis, the process by which cancer cells migrate and establish tumors throughout the body. A new study from Rice University cancer researchers details the workings of key genetic circuits involved in metastasis. (Source: University)As researchers delve deeper into cancer, they continually find how complex it is and how it relies on signals coming from various entities to sense its environment and plot its next moves. Will it remain dormant in a single tumor or will it metastasize and move throughout the body to infect other areas?

This well-honed activity is what makes cancer so deadly. More than 90 percent of the people who die from cancer die from metastasis, not the original tumor. It also makes cancer highly evasive to those trying to put an end to it. Understanding how cancer cells change their activity and their characteristics could go a long way to understanding how it operates and give researchers new hope in finding ways to prevent its spread through metastasis.

But to break the cancer code, researchers have to break through its complexity, to simplify its operation.

Now, cancer researchers from Rice University’s Center for Theoretical Biological Physics (CTBP) have taken a step in this direction and deciphered the operating principles of a genetic switch that cancer cells use to decide when to metastasize and invade other parts of the body. The study found that the on-off switch’s dynamics also allows a third choice that lies somewhere between “on” and “off.” The extra setting both explains previously confusing experimental results and opens the door to new avenues of cancer treatment.

The work is described in “MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination,” which appeared in the early on line edition of the Proceedings of the National Academy of Sciences.

Eshel Ben-JacobAccording to co-author Eshel Ben-Jacob, a senior investigator at Rice’s CTBP and a professor of physics of complex systems and professor of physics and astronomy at Tel Aviv University, Israel, the team was able to “strip away the complexity of cancer” and determine its core decision network. This could provide crucial insight into how cancer determines when and how to change states.

This stripping away of the complexity of cancer to its “first principles” of operation is a key, Ben-Jacob said.

“It represents a very different approach to understanding the cancer,” he explained. Rather than treating the cancer as it presents itself, the researchers were able to determine cancer’s core decision network, which opens up possibilities for turning it onto itself or exposing it to the immune system.

In the PNAS paper, Ben-Jacob and colleagues José Onuchic, Herbert Levine, Mingyang Lu and Mohit Kumar Jolly describe a new theoretical framework that allowed them to model the behavior of microRNAs in decision-making circuits. To test the framework, they modeled the behavior of a decision-making genetic circuit that cells use to regulate the forward and backward transitions between two different cell states, the epithelial and mesenchymal.

Known respectively as the E-M transition (EMT) and the M-E transition (MET), these changes in cell character are vital for embryonic development, tissue engineering and wound healing. The EMT transition is also a hallmark of cancer metastasis, where cancer cells can co-opt the process to allow carcinoma tumor cells to break away, migrate to other parts of the body and establish a new tumor.

To find ways to shut down metastasis, cancer researchers have conducted dozens of studies about the genetic circuitry that activates the EMT. These studies showed a two-component genetic switch is the key for both the EMT and the MET.

The Rice team also found that during the EMT, some cells form a third type, a hybrid character that is endowed with a special mix of both epithelial and mesenchymal abilities, including group migration. Ben-Jacob said the hybrid, or partially on-off state of the decision switch, also supports cancer metastasis by enabling collective cell migration and by imparting stem cell properties that help migrating cancer cells evade the immune system and anticancer therapies.

“The state in the middle is related to the ability of some of the cells to enter into cancer stem cells. That is very important because they can then differentiate to different types of cancer,” he said. “They can also give rise to different types of motility. They can have intermediate states of metabolism. It gives the overall system much more flexibility than ‘on or off.’”

“Now that we understand what drives the cell to select between the various states, we can begin to think of new ways to outsmart cancer,” Ben-Jacob said. “We can think about coaxing the cancer to make the decisions that we want, to convert itself into a state that we are ready to attack with a particularly effective treatment. We can start to apply different signals that would confuse the cancer” possibly turning it onto itself or exposing it to the immune system.

Ben-Jacob said this work fits nicely with his previous studies with Onuchic into the collective decision-making processes of bacteria and into new strategies to combat cancer by timing the delivery of multiple drugs to interrupt the decision-making processes of cancer.

The idea is to attack the core of cancer’s operating, communications and command system.

“The real way to fight cancer is to see it as a battlefield and you conduct a cyber war against the cancer,” Ben-Jacob added. “Against its communication and control.”