Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumor and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall.

“The elephant in the room is that we didn’t really understand how cancer cells were able to survive and thrive in this inflammatory environment,” says Samuel Bakhoum, a physician-scientist at MSK and a member of the Human Oncology and Pathogenesis Program.

According to a new study from Dr. Bakhoum’s lab published December 28 in the journal Cancer Discovery, the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighboring immune cells.

The findings help to explain why some tumors do not respond to immunotherapy, and — equally important — suggest ways to sensitize them to immunotherapy.

Detecting Dangerous DNA

The warning system Dr. Bakhoum studies is called cGAS-STING. When DNA from a virus (or an unstable cancer chromosome) lands in a cell’s cytoplasm, cGAS binds to it, forming a compound molecule called cGAMP, which serves as a warning signal. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral invader.

In addition, much of the cGAMP also travels outside the cell where it serves as a warning signal to neighboring immune cells. It activates their STING pathway and unleashes an immune attack against the virally infected cell.

Previous work from the Bakhoum lab had shown that cGAS-STING signaling inside of cancer cells causes them to adopt features of immune cells — in particular, the capacity to crawl and migrate — which aids their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process. The new research shows how the cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. A scissor-like protein shreds the signals, providing a second way the cells can thwart the threat of immune destruction.

Examples of human triple negative breast cancer staining negative (left) and positive (right) for ENPP1 expression. Examples of human triple negative breast cancer staining negative (left) and positive (right) for ENPP1.

The scissor-like protein that coats cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 chops it up and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also quells inflammation.

Through a battery of experiments conducted in mouse models of breast, lung, and colorectal cancers, Dr. Bakhoum and his colleagues showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning it on suppresses immune responses and increases metastasis; turning it off enables immune responses and reduces metastasis.

The scientists also looked at ENPP1 in samples of human cancers. ENPP1 expression correlated with both increased metastasis and resistance to immunotherapy.

Empowering Immunotherapy

From a treatment perspective, perhaps the most notable finding of the study is that flipping the ENPP1 switch off could increase the sensitivity of several different cancer types to immunotherapy drugs called checkpoint inhibitors. The researchers showed that this approach was effective in mouse models of cancer.

Several companies — including one that Dr. Bakhoum and colleagues founded — are now developing drugs to inhibit ENPP1 on cancer cells.

Dr. Bakhoum says it’s fortunate that ENPP1 is located on the surface of cancer cells since this makes it an easier target for drugs designed to block it.

It’s also relatively specific. Since most other tissues in a healthy individual are not inflamed, drugs targeting ENPP1 primarily affect cancer.

Finally, targeting ENPP1 undercuts cancer in two separate ways: “You’re simultaneously increasing cGAMP levels outside the cancer cells, which activates STING in neighboring immune cells, while you’re also preventing the production of the immune-suppressive adenosine. So, you’re hitting two birds with one stone,” Dr. Bakhoum explains.

The pace of the research has been incredibly fast, he says. “One of the things I would be really proud of is if this research ends up helping patients soon, given that we only just started this work in 2018.”

He hopes there will be a phase I clinical trial of ENPP1 inhibitors within a year.

While other studies have found an association between vaping and mental impairment in animals, the URMC team is the first to draw this connection in people. Led by Dongmei Li, Ph.D., associate professor in the Clinical and Translational Science Institute at URMC, the team mined data from two major national surveys.

“Our studies add to growing evidence that vaping should not be considered a safe alternative to tobacco smoking,” said study author Li.

The studies, published in the journals Tobacco Induced Diseases and Plos One, analyzed over 18,000 middle and high school student responses to the National Youth Tobacco Survey and more than 886,000 responses to the Behavioral Risk Factor Surveillance System phone survey from U.S. adults. Both surveys ask similar questions about smoking and vaping habits as well as issues with memory, attention and mental function.

Both studies show that people who smoke and vape — regardless of age — are most likely to report struggling with mental function. Behind that group, people who only vape or only smoke reported mental fog at similar rates, which were significantly higher than those reported by people who don’t smoke or vape.

The youth study also found that students who reported starting to vape early — between eight and 13 years of age — were more likely to report difficulty concentrating, remembering, or making decisions than those who started vaping at 14 or older.

“With the recent rise in teen vaping, this is very concerning and suggests that we need to intervene even earlier,” said Li. “Prevention programs that start in middle or high school might actually be too late.”

Adolescence is a critical period for brain development, especially for higher-order mental function, which means tweens and teens may be more susceptible to nicotine-induced brain changes. While e-cigarettes lack many of the dangerous compounds found in tobacco cigarettes, they deliver the same amount or even more nicotine.

While the URMC studies clearly show an association between vaping and mental function, it’s not clear which causes which. It is possible that nicotine exposure through vaping causes difficulty with mental function. But it is equally possible that people who report mental fog are simply more likely to smoke or vape — possibly to self-medicate.

Li and her team say that further studies that follow kids and adults over time are needed to parse the cause and effect of vaping and mental fog.

In addition to Li, authors of the youth study include Catherine Xie, and Zidian Xie, Ph.D. For the adult study, Li was joined by co-authors Zidian Xie, Ph.D., Deborah J. Ossip, Ph.D. Irfan Rahman, Ph.D., and Richard J. O’Connor, Ph.D. Both studies were funded by the National Cancer Institute and the U.S. Food and Drug Administration’s Center for Tobacco Products.

Story Source:

Materials provided by University of Rochester Medical Center. Original written by Susanne Pallo. Note: Content may be edited for style and length.

Quantum dots in two dimensional array is a leap ahead

One of the key features of the devices is the two-dimensional array of quantum dot. Or more precisely, a two by two lattice of quantum dots. “What we have shown is that we can realize single electron control in every single one of these quantum dots. This is very important for the development of a qubit, because one of the possible ways of making qubits is to use the spin of a single electron. So reaching this goal of controlling the single electrons and doing it in a 2D array of quantum dots was very important for us,” says Fabio Ansaloni, former PhD student, now postdoc at center for Quantum Devices, NBI.

Using electron spins has proven to be advantageous for the implementation of qubits. In fact, their “quiet” nature makes spins weakly interacting with the noisy environment, an important requirement to obtain highly performing qubits.

Extending quantum computers processors to the second dimension has been proven to be essential for a more efficient implementation of quantum error correction routines. Quantum error correction will enable future quantum computers to be fault tolerant against individual qubit failures during the computations.

The importance of industry scale production

Assistant Professor at Center for Quantum Devices, NBI, Anasua Chatterjee adds: “The original idea was to make an array of spin qubits, get down to single electrons and become able to control them and move them around. In that sense it is really great that Leti was able to deliver the samples we have used, which in turn made it possible for us to attain this result. A lot of credit goes to the pan-European project consortium, and generous funding from the EU, helping us to slowly move from the level of a single quantum dot with a single electron to having two electrons, and now moving on to the two dimensional arrays. Two dimensional arrays is a really big goal, because that’s beginning to look like something you absolutely need to build a quantum computer. So Leti has been involved with a series of projects over the years, which have all contributed to this result.”

The credit for getting this far belongs to many projects across Europe

The development has been gradual. In 2015, researchers in Grenoble succeeded in making the first spin qubit, but this was based on holes, not electrons. Back then, the performance of the devices made in the “hole regime” were not optimal, and the technology has advanced so that the devices now at NBI can have two dimensional arrays in the single electron regime. The progress is threefold, the researchers explain: “First, producing the devices in an industrial foundry is a necessity. The scalability of a modern, industrial process is essential as we start to make bigger arrays, for example for small quantum simulators. Second, when making a quantum computer, you need an array in two dimensions, and you need a way of connecting the external world to each qubit. If you have 4-5 connections for each qubit, you quickly end up with a unrealistic number of wires going out of the low-temperature setup. But what we have managed to show is that we can have one gate per electron, and you can read and control with the same gate. And lastly, using these tools we were able to move and swap single electrons in a controlled way around the array, a challenge in itself.”

Two dimensional arrays can control errors

Controlling errors occurring in the devices is a chapter in itself. The computers we use today produce plenty of errors, but they are corrected through what is called the repetition code. In a conventional computer, you can have information in either a 0 or a 1. In order to be sure that the outcome of a calculation is correct, the computer repeats the calculation and if one transistor makes an error, it is corrected through simple majority. If the majority of the calculations performed in other transistors point to 1 and not 0, then 1 is chosen as the result. This is not possible in a quantum computer since you cannot make an exact copy of a qubit, so quantum error correction works in another way: State-of-the-art physical qubits do not have low error rate yet, but if enough of them are combined in the 2D array, they can keep each other in check, so to speak. This is another advantage of the now realized 2D array.

The next step from this milestone

The result realized at the Niels Bohr Institute shows that it is now possible to control single electrons, and perform the experiment in the absence of a magnetic field. So the next step will be to look for spins — spin signatures — in the presence of a magnetic field. This will be essential to implement single and two qubit gates between the single qubits in the array. Theory has shown that a handful of single and two qubit gates, called a complete set of quantum gates, are enough to enable universal quantum computation.