Recent research has elucidated a pathway to better understanding cancer cell function. Researchers at Rice University have discovered how cancer cells decide to stay where they are or move about the body. They found that there is a molecular “on” and “off” switch that cancer cells use to determine their fate. Evidently, there is an on or off state for metastasis (migration), but also a third possibility, according to this recently-discovered molecular data. The third possibility allows for an in-between state that explains previously conflicting data. This in turn poses new avenues of therapies to treating cancer. The current study is available in the Proceedings of the National Academy of Sciences.
According to co-author Eshel Ben-Jacob, a senior investigator at Rice’s Center for Theoretical Biological Physics (CTBP) and adjunct professor of biochemistry and cell biology at Rice, “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. 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.”
This study involves microRNAs, which often inhibit the translation of a particular protein. In this current research, Ben-Jacob and CTBP colleagues José Onuchic, Herbert Levine, Mingyang Lu and Mohit Kumar Jolly have presented a new theoretical basis that allows them to observe the behavior of microRNAs in so called decision-making circuits. To test their model, they made use of genetic circuits that use ability to switch between a differential state in cell type from epithelial to mesenchyal cell types. The transitions are referred to as epithelial to mesenchyal transitions (EMT) and mesenchyal to epithelial transitions (MET). A mixture of these cell types generates different forms of cancer metastasis. Currently, it is known that the EMT stage is a hallmark of cancer metastasis. To further elucidate pathways, the Rice researchers are studying what activates the genetic circuitry that further activates the EMT. From previous studies, there is a two-component genetic switch to both EMT and MET. Technically speaking, this involves two proteins, known as SNAIL and ZEB. Snail corresponds to micorRNAA34 (SNAIL/miR34) and ZEB corresponds to microRNA20 (ZEB/miR200). The presence of one inhibits the presence of the other.
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To better understand this particular biological situation, it is important to note that the mesenchymal cell state (cancer metastasis) of both SNAIL and ZEB are present in high levels. For the epithelial state, microRNA partners dominate, and neither ZEB or SNAIL are present in high levels. Essentially, you have two genes that are mutually limiting. Think of it as having gene A, which is highly expressed that inhibits gene B. Otherwise, gene B is highly expressed and inhibits gene A. This is what happens with ZEB and miR200. One of these is on and the other is off. This is what makes the on/off switch.
It turns out that SNAIL and miR34 interact more weakly. So, they can be present at the same time. What happens with them depends on which proteins are present and which genes are expressed (cancer genes).
Ben-Jacob points out, “One of the most important things the model showed us was how SNAIL and miR34 act as an integrator. 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.”
The researchers discovered that there was an intermediate function, which is termed a “ternary,” or three-way switch. This function relates to the fact that ZEB has the ability to turn itself on due to a positive feedback system. This allows a cell to keep intermediate levels of all four proteins required for the switch. Ben-Jacob notes that 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 researchers have an idea of the various states, they can begin to think of what they can do to manipulate cancer cell states with various drug therapies.