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When cancer cells decide to metastasize and invade other parts of the body, they rely on a genetic on-off switch. Now physicists say they’ve decoded the “logic” behind the process.

The on-off switch’s dynamics also allow 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.

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“Cancer cells behave in complex ways, and this work shows how such complexity can arise from the operation of a relatively simple decision-making circuit,” says study co-author Eshel Ben-Jacob, a senior investigator at Rice University’s Center for Theoretical Biological Physics and adjunct professor of biochemistry and cell biology.

“By stripping away the complexity and starting with first principles, we get a glimpse of the ‘logic of cancer’—the driver of the disease’s decision to spread.”

In a study published in the Proceedings of the National Academy of Sciences, Ben-Jacob and colleagues 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.

A hybrid state

Known respectively as the E-M transition (EMT) and the M-E transition (MET), these changes in cell state are vital for embryonic development, tissue engineering, and wound healing.

During the EMT, some cells also form a third state, a hybrid that is endowed with a special mix of both epithelial and mesenchymal abilities, including group migration.

The EMT transition is also a hallmark of cancer metastasis. Cancer cells co-opt the process to allow 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.

One clear finding from previous studies is that a two-component genetic switch is the key to both the EMT and MET. The switch contains two specialized pairs of proteins. One pair is SNAIL and microRNA34 (SNAIL/miR34), and the other is ZEB and microRNA200 (ZEB/miR200).

Each pair is “mutually inhibitory,” meaning that the presence of one of the partners inhibits the production of the other.

Multiple cues

In the mesenchymal cell state—the state that corresponds to cancer metastasis—both SNAIL and ZEB must be present in high levels. In the epithelial state, the microRNA partners dominate, and neither ZEB nor SNAIL is available in high levels.

“Usually, if you have two genes that are mutually limiting, you have only two possibilities,” Ben-Jacob says. “In the first case, gene A is highly expressed and inhibits gene B. In the other, gene B is highly expressed and it inhibits A. This is true in the case of ZEB and miR200.

“One of these is ‘on’ and the other is ‘off,’ so it’s clear that this is the decision element in the switch.”

SNAIL and miR34 interact more weakly. As a result, both can be present at the same time, with the amount of each varying based upon inputs from a number of other proteins, including several other cancer genes.

“One of the most important things the model showed us was how SNAIL and miR34 act as an integrator,” Ben-Jacob says. “This part of the circuit is acted on by multiple cues, and it integrates those signals and feeds information into the decision element. It does this based upon the level of SNAIL, which activates ZEB and inhibits miR200.”

Outsmart cancer

In modeling the ZEB/miR200 decision circuit, the team found that it operates as a “ternary”, or three-way, switch. The reason for this is that ZEB has the ability to activate itself by a positive feedback loop, which allows the cell to keep intermediate levels of all four proteins in the switch under some conditions.

Ben-Jacob says the hybrid, or partially on-off state, 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.

“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 says. “We can think about coaxing the cancer to make the decision that we want, to convert itself into a state that we are ready to attack with a particularly effective treatment.”

The National Science Foundation, the Cancer Prevention and Research Institute of Texas, and the Tauber Family Funds at Tel Aviv University supported the work.

Source: Rice University