Sleeper cells: New neural stem cell state gives insight into cancer

ASU researchers discover and explore new resting phase of stem cells that could help put brain tumors to sleep

June 24, 2021

The human body contains approximately 200 different kinds of cells, including many kinds of stem cells that have the potential to turn into a variety of specialized cells. Probing into the life cycle states or phases of these cells is important to understanding and treating diseases like dementia and cancer.

Christopher Plaisier, an assistant professor of biomedical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, and Samantha O’Connor, a biomedical engineering doctoral student in the Plaisier Lab, are leading research into a new state of the stem cell life cycle that could be the key to unlocking new methods of brain cancer treatment. Their work was recently published in the research journal Molecular Systems Biology. An abstract view of cell cycle data. Arizona State University biomedical engineering researchers developed a new cell classifier tool that takes a higher-resolution look at the life cycle of neuroepithelial stem cells, which led to the discovery and exploration of a new resting phase called Neural G0. This knowledge could help scientists to better understand glioma brain tumors and develop new methods of treatment. Graphic by Rhonda Hitchcock-Mast and Christopher Plaisier Download Full Image

“The cell cycle is such a well-studied thing, and yet here we are looking at it again for the umpteenth time and a new phase pops out at us,” Plaisier said. “Biology always has new insights to show us; you just have to look.”

Taking a closer look

The spark for this discovery came through a collaboration with Patrick Paddison, an associate professor at the Fred Hutchinson Cancer Research Center in Seattle, and Dr. Anoop Patel, an assistant professor of neurological surgery at the University of Washington who is also involved in the Fred Hutchinson Cancer Research Center. Paddison’s team was looking at genes that play a role in stem cells’ growth in the brain as a potential path to a treatment for neurodegeneration.

“The primary feature of any cancer is that the cells are proliferating,” Plaisier said. “If we could get in there and figure out what the mechanisms are, that might be a place to slow them down.

"In cases where you have neurodegeneration, having stem cells that proliferate is potentially beneficial. The one problem with that is it's also similar to what happens when cancer cells increase rapidly. It's two sides of the same coin.”

Paddison’s team called upon Plaisier to help analyze their brain stem cell data characterized through a process called single-cell RNA sequencing.

“That data turned out to be pretty amazing,” Plaisier said. “It mapped out into this beautiful circular pattern that we identified as all of the different phases of the cell cycle.”

By taking a closer look at the data, they found a new cell phase that had never been observed before in neuroepithelial stem cells, which they call Neural G0. This discovery sparked a six-year research project to study the new phase and determine what it means for the progression of diseases, particularly glioma brain tumors.

Understanding the life of a cell

Our body’s cells go through four main phases: grow, copy the genetic material stored in the nucleus, grow again and divide into two new cells. These phases are known as G1, S, G2 and M.

Many cells stop after their initial growth and enter an alternate state after G1, which is a sleep-like state called G0. In this state, cells are dormant or go about their normal functions without preparing to divide again.

Cancer arises when cells develop mutations that cause them to break out of the G0 state and grow and divide very quickly.

Like other types of cells, stem cells also have resting states. One is known as quiescence, which is the state where cells live independently from the cell cycle, though they can hop back into the cell cycle given the right cues. Neural G0 is similar to this quiescent state that other stem cells go through, but it has features particular to neuroepithelial cells, a type of stem cell that is destined to turn into certain brain cells.

Glioma tumors arise in the brain from neuroepithelial cells entering the growth and division phase at higher rates. Studying the life cycle of these cells is an important area of research for finding ways to combat cancer cell proliferation.

Developing new tools

Researchers use tools called classifiers to assign a cell cycle phase to individual cells based on the state of RNA messenger substances inside the cell.

Many existing cell cycle classifiers pick out only the major steps in a cell’s life cycle, like a map of the world that depicts only outlines of the continents. However, just as we know there are far more details that can be mapped on a continent, it turns out there is much more to see within the individual stages of the cell cycle.

“We were able to pick out phases that are glommed together in the other cell cycle classifiers,” Plaisier said. “That potentially has several different uses."

The tool O’Connor developed — called ccAF, or cell cycle ASU/Fred Hutchinson to represent the collaboration between the two institutions — takes a closer, “high-resolution” look at what’s happening within the growth cycles of stem cells and identifies genes that can be used to track progress through the cell cycle.

“Our classifier gets deeper into the cell cycle because there could be pieces we’re capturing that have important implications for disease,” O’Connor said.

While it is possible to pick out the cell phases using complicated techniques such as applying fluorescent markers on actual cells, Plaisier and O’Connor found the Neural G0 state purely through looking at data, a much simpler process.

Plaisier and O’Connor are making the ccAF classifier tool open source and available in a variety of formats for anyone studying single-cell RNA sequencing data to ease into the process of studying cell cycles.

The tool could also be used to study other types of stem cells that potentially have yet-to-be-discovered G0 states similar to or completely different from the Neural G0 state of neuroepithelial stem cells.

Applying new knowledge to study cancer

When Plaisier and O’Connor used the ccAF tool to analyze cell data for glioma tumors, they found the tumor cells were often either in the Neural G0 or G1 growth state. And as tumors become more aggressive, fewer and fewer cells remain in the resting Neural G0 state. This means more and more cells are proliferating and growing the tumor.

They correlated this data with the prognosis for patients with glioblastoma, a particularly aggressive type of brain tumor. Those with higher Neural G0 levels in tumor cells had less aggressive tumors.

They also found that the quiescent Neural G0 state is independent of a tumor’s proliferation rate, or how fast its cells divide and create new cells.

“That was an interesting finding from our results, that quiescence itself could be a different biological process,” Plaisier said. “It’s also a potential point where we could look for new drug treatments. If we could push more cells into that quiescent state, the tumors would become less aggressive.”

Current cancer drug treatments focus on killing cancer cells. However, when the cancer cells are killed, they release cell debris into the surrounding area of the tumor, which can cause the remaining cells to become more resistant to the drugs.

“So, instead of killing the cells, if we put them to sleep it could potentially be a much better situation,” Plaisier said.

For example, if a glioblastoma tumor is cut out, a drug that promotes the quiescent state could be introduced to the tumor site to prevent any remaining cells from growing and causing a tumor to recur.

“You can maintain what’s there, and it wouldn’t get worse,” O’Connor said. “It’s a different idea of how to treat cancer.”

Further exploration

With the possibility of new cancer treatments in mind, Plaisier and O’Connor are exploring which genes are responsible for pushing cells into a quiescent state and how this function can be used for new therapies for glioblastomas, the most common and deadly brain tumor.

This research is part of a new project supported by a National Institutes of Health R01 grant to better define G0-like states in glioblastoma brain tumors. This NIH grant from the National Institute for Neurological Disorders and Stroke supports the cross-disciplinary collaboration between the Plaisier, Paddison and Patel labs to create a map of gene interactions that govern tumor regulation of G0-like states and explain therapy resistance and glioblastoma recurrence.

With their ccAF tool, they were also able to find new states at the beginning and end of the cell cycle that exist between the commonly known states.

“We’re starting to think about ways to dig into those and learn more about the biology of the entry and exit from the cell cycle because those are potentially really important points where the cells will either go into the G1 state or G0,” Plaisier said.

Figuring out what triggers a cell to enter the division cycle or remain in a G0 resting state could help researchers understand the processes behind tumor growth.

“The primary feature of any cancer is that the cells are proliferating,” Plaisier said. “If we could get in there and figure out what the mechanisms are, that might be a place to slow them down.”

Monique Clement

Lead communications specialist, Ira A. Fulton Schools of Engineering


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Arizona's economic forecast: Will the state see a rebound in summer tourism?

June 25, 2021

ASU economy and tourism experts weigh in

Although metro Phoenix may not always be a top destination during Arizona's hot summer months, cooler destinations in the state are — like the Grand Canyon, ranked third by U.S. News and World Report's "Best Family Summer Vacations” list.

But despite the Valley’s high temperatures, the appeal of traveling and enjoying leisure activities and entertainment around the state exists and contributes to the state’s overall tourism tax revenue. In 2019, prior to the pandemic, Arizona’s estimated tax revenue from lodging, restaurants and bars, retail and amusement was well over $67 million in June alone, according to the Arizona Office of Tourism. So what’s Arizona’s summer economic forecast for 2021 after a cautious pandemic year? 

To answer those questions, ASU News spoke to Dennis Hoffman, professor in the Department of Economics at the W. P. Carey School of Business and the director of the L. William Seidman Research Institute, and Nicholas Wise, assistant professor in the School of Community Resources and Development in the Watts College of Public Service and Community Solutions, about what it will take for Arizona’s tourism industry to bounce back.

Question: As COVID-19 guidelines ease up, will there be a stronger demand for summer travel this year, and will Arizona start seeing an economic rebound? 

, professor of economics in the W. P. Carey School of Business at ASU.

Dennis Hoffman

Hoffman: Travel is picking up around the nation, but the impact for this summer in Arizona remains a bit cloudy compared with last summer. While the pandemic dampened Arizona resident travel, it is likely that a higher share of Arizona resident travelers stayed in the state rather than California, the typical summer destination.

Historically, Arizona slows significantly during the summer months as folks travel out of state or simply stay home and avoid the heat. I expect this summer will be closer to normal but perhaps not quite normal. Historically, the winter and spring months are most important for tourist-generated tax revenues. The stimulus money paid in the spring may help boost spending this summer, but I expect a below-average year for folks traveling from out of state/country to the Grand Canyon. Look to summer 2022 for essentially a full return to normal.

Q: How long will the hospitality and travel industry continue practicing COVID-19 safety practices? Do you think those practices will encourage tourism?

Wise: While the mask mandate has been relaxed and public health experts are advising it is safe to no longer wear a mask indoors if you are fully vaccinated, this does not apply to transportation. Because the travel and hospitality industries see people gathered in close proximity, it is expected that wearing a mask at airports and during flights will continue at least until the 13th of September this year, according to the TSA. The same applies to public transport, and it is safe practice to wear a mask in taxis or shared van shuttles, as this is how many people will likely travel from the airport to their hotel. 

With tourism and hospitality, you interact with people from across the country and world, and policies can be vastly different, depending on where someone is from. It seems that each company is setting guidelines and continuing COVID safety practices to ensure everyone feels safe on their terms, but a challenge is balancing this with what consumers want, demand and desire. Consumers may see the vaccine as a quick solution to returning to travel and may make plans, but I think that consumers will also be aware that hotels and restaurants in the destinations they visit are looking out for their safety. I don’t think this will deter tourism, but will encourage it because continued safety practices for many might be that peace of mind they are looking for as they look to get out and visit new places again. But we should keep in mind that different companies have different policies and practices.

Q: The hospitality industry has been struggling to find workers. Will this impact the possibility of an economic rebound this summer? 

Hoffman: The challenge with employment in hospitality will not likely become severe until fall and winter when the seasonal tourist season kicks into full swing. Hospitality businesses did struggle a bit this spring with finding help. People continue to be hesitant working in people-facing businesses. Child care costs are also a concern. And it is likely that a significant share of hospitality workers are undocumented. That adds another friction. I sense also that people are reassessing their chosen occupational pursuits, considering job switching, retraining, etc.

 is an assistant professor in the School of Community Resources and Development at ASU.

Nicholas Wise

Wise: Many of the most vulnerable in our society who prior to the pandemic had worked in lower-wage jobs in the tourism and hospitality industries saw jobs cut as businesses needed to save money and preserve finances. Not everyone had the opportunity to use this past year to up-skill or go back to college or university. This damaging decline put families working hourly paid jobs in a difficult situation without opportunity or financial resources to invest in training or education, or use any savings to invest in a business to capitalize on in the future. 

This is a time to reflect on the social inequalities and work to set policies that focus on equity and justice to ensure opportunities for local communities and not just corporate businesses. As jobs come back in demand, tourism numbers grow, profits are achieved again — what is supporting this growth is a labor force that keeps these companies and industries moving forward to meet consumer demand. 

Q: What type of travel incentives will tourists likely see from hotels, airlines and other businesses?

Wise: The tourism and hospitality industries were some of the hardest-hit industries, and several airlines extended their frequent flier awards a year so that the consumer would not lose out on their loyalty benefits. It can be difficult for a company to offer a lot of incentives due to financial losses in 2020 into 2021. Consumers recognize this, and as travel opens up more and more, what companies can do is provide that sense of welcoming back to consumers. Demand is increasing, so this can bring new opportunities once again for businesses in the destination. I think businesses in the destinations will offer incentives — because they want to attract new and existing clientele back to their service offering. For airlines and hotels, it is the chance to resume their services as they are central to how we get somewhere and then we need to stay somewhere.

Q: How will the demand for domestic tourism compare with international tourism?

Wise: There have been limited flights internationally since the pandemic. This means that prices to fly internationally might not be as competitive. As the airlines look at search trends and determine where people want to go, they will likely then respond by expanding service offerings. At the moment, I believe that initially domestic tourism will benefit in this recovery period due to regularly scheduled services that were maintained through the pandemic. As airlines increase international routes, this may spark more competition between airlines to cater to international tourism more in the future.

Q: How long will it take for Arizona to bounce back from the damaging tourism decline in 2020?

Wise: This is a difficult question, and time will tell. It will likely happen in different phases across the state based on a destination's capacity to welcome back tourists. You could say we are seeing a bounce back already in parts of the Valley. For instance, it was reported in the news that there are now more restaurants open in Phoenix than pre-pandemic. The number of people passing through airport security to board flights has significantly increased since this time last year, looking at daily TSA passenger figures. We are still not at 2019 numbers, but increases over the past few months are certainly evident. 

There is also a noticeable difference in the amount of people out in the city. It was reported that resorts in Scottsdale are seeing increased demand as people look to go out and travel again, with some resorts reaching 90% capacity over recent weekends. Times of decline are times to really strategize, and we see this with new hotels being constructed during the pandemic. These projects create and maintain jobs in the construction industry, the same with planning new restaurants and fixing up the spaces, as these business owners or investors are planning for the right time to open.

Hoffman: There is every reason to believe that spring 2022 will see tourism numbers back to 2019 levels. This will be welcome to industry participants and will set the stage for future growth trends that match pre-pandemic levels. But any indication that the virus is making a comeback or that vaccines are becoming less effective will stifle growth in this area significantly. But with each passing month, pandemic memories should fade and preferences for travel should reemerge.

Top photo of the Grand Canyon courtesy of Media relations officers Jimena Garrison and Nikai Salcido contributed to this article.