Transformative awards for Mocarski's malleable cells, lung fibrosis

The National Institutes of Health has announced a five-year, $1.9 million Transformative Research Award to Emory virologist Edward Mocarski, PhD for his work on how the mechanisms of programmed cell death can be subverted. Mocarski is Robert W. Woodruff professor of microbiology and immunology at Emory University School of Medicine and Emory Vaccine Center. His research, which originated in probing how cells commit suicide when taken over by viruses, could lead to advances in regenerative medicine and organ transplant. The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nine “high-risk-, high-reward” Transformative Research Awards (13 recipients) announced by the NIH on October 6. In the same group this year, Thomas Barker in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University received a Transformative Research Award for his research on mechanosensors + pulmonary fibrosis. The Transformative Research Award program supports “exceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested.” Emory has achieved only one other TRA since the program was established in 2009: Shuming Nie's project on imaging to guide cancer surgery. “This Transformative award was made possible because of the creative and engaged graduate students and postdoctoral fellows I have had working with me at Emory,” Mocarski says. In 2011, Mocarski, working with former graduate student William Kaiser and Emory geneticist Tamara Caspary showed that two complementary forms of programmed cell death, necrosis and apoptosis, can be genetically excised from mice, leaving a viable animal with a functioning immune system. These findings are yielding additional fruit. Mocarski’s research indicates that cells from these genetically altered mice are unexpectedly malleable, in that they are easier to reprogram into induced pluripotent stem cells. Once reprogrammed, induced pluripotent stem cells (iPS cells) can be directed to become cells of almost any tissue, making them promising potential tools for the treatment of many diseases. The genetically altered mice are also less susceptible to deadly inflammation and more readily accept bone marrow transplants. The Transformative project’s aims are to exploit these findings and test the ability of drugs that interfere with programmed cell death to facilitate tissue regeneration, iPS cell reprogramming and transplant.      

Cancer metastasis: isolating invasive cells with a color change

At Winship Cancer Institute, Adam Marcus and Jessica Konen have developed a tool for probing how invasive cells are different, which could lead to new ways to fight cancer metastasis. In the video, check out how they track the behavior of apparently devious "leader cells".

Tools for illuminating brain function make their own light

Hey optogenetics fans, cut (or temporarily put aside) the fiber optic cable. Flexible tools allow the choice between activation by light or an external chemical.

Winship Cancer Institute

Cancer metastasis: isolating invasive cells with a color change

The capacity of cancer cells to spread throughout the body and invade new tissues – to become metastatic — makes them deadly. What makes metastatic cells different? Scientists at Winship Cancer Institute of Emory University have developed a technique for isolating individual cells that display invasive behavior out of a large group in culture by changing their color.

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Adaptive mutation mechanism may drive some forms of antibiotic resistance

Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results were published Tuesday, August 25 in PLOS Genetics.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first. Read more

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CMV reactivation warps immune system after HSCT

As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.

Leslie Kean, MD, PhD

The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.

CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.

The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more

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Low doses of imatinib can stimulate innate immunity

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.

The results were published this week in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.

Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.

Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more

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BAI1: a very multifunctional protein

Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.

Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.

The findings may have implications for developing treatments for neurological diseases, because BAI1 is part of a protein regulatory network neuroscientists think is connected with autism spectrum disorders.

The results were published online March 9 in Journal of Clinical Investigation.

Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.

The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didn’t develop tumors any faster than normal, and they didn’t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1’s role in regulating blood vessel growth. What they did have was problems with spatial memory.

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Rules of thumb for drug discovery

People interested in drug discovery may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. They basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelines have been the topic of much debate among medicinal chemists and pharmacologists.

The namesake for this set of rules, Chris Lipinski, will be speaking at Winship Cancer Institute Wednesday afternoon (4:30 pm, Nov 5, C5012) on “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there, he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

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Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

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Shoutout to Not a Mad Scientist

Cheers to microscopist and Winship Cancer Institute researcher Adam Marcus, who has started his own blog called “Not a Mad Scientist.” His first post talks about his educational outreach activities:

I have a super huge, somewhat tattered, and quite ugly suitcase that sits in my office.  This suitcase is not packed with clothes or extra large toiletries, but contains a pretty cool microscope, computer, and some shipping foam. Every few weeks I wheel it into the hallway, then into the elevator, and eventually into my car. The suitcase and I end up in Kindergarten-12th grade classrooms where I try to teach children something about science that they would not normally see.  I try to give them something different, something real, something scientific. I have seen over 3,000 children in about 200 classrooms in rural and urban schools, from pre-K to 12th grade…

We had a post in October about his lab’s research investigating Withania somnifera, a root used in Indian traditional medicine that contains potential tools for stopping breast cancer invasion and metastasis. Marcus’ blog has a collection of microscope movies, which we hope he will keep current.

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Without intent, yet malignant

Brain cancer doesn’t have a purpose or intent. It’s just a derangement of molecular biology, cells that keep growing when they’re not supposed to.

But it’s difficult not to think in terms of purpose or intent when looking at what cancers do.  For example, Winship Cancer Institute scientists Abdessamad (Samad) Zerrouqi, Beata Pyrzynska, Dan Brat and Erwin Van Meir have a recent paper in Cancer Research examining how glioblastoma cells regulate the process of blood clotting.*

Blood clots, often in the legs, are a frequent occurrence in patients fighting glioblastoma, the most common and the most aggressive form of brain cancer. Zerrouqi and Van Meir show that a tumor suppressor gene (p14ARF) that is often mutated in glioblastoma stops them from activating blood clotting. Take away the gene and glioblastoma cells activate the clotting process more.

At first glance, a puzzle emerges: why would a cancer “want” to induce blood clots? Cancer cells often send out growth factors that stimulate the growth of new blood vessels (angiogenesis). The cells are growing fast, thus they need their own blood supply. Activating clotting seems contradictory: why build a new highway and then induce a traffic jam?


The two left arrows indicate clots causing necrosis around the vessels. Cells at the edge of the necrotic zone (right arrow) tend to be more proliferative and invasive. Image courtesy of Zerrouqi.

In a way, tumor cells are acting somewhat Nietzschean, blindly managing their own evolution according to the principle “Whatever doesn’t kill me makes me stronger.”

Blood clots lead to both destruction of the healthy and tumor tissue and hypoxia, a shortage of oxygen that drives more aggressiveness in the tumor. The clots create “micro-necroses” at the leading edge of the tumor that over time probably fuse and create a big central necrosis.

“The paradox is that the tumor kills itself and the normal brain, yet the capacity of doing this is the hallmark of the most malignant form of this tumor,” Van Meir says.

“The advantage of tumoral thrombosis will be selection of cells to progress to higher aggressiveness: infiltrative,  resistant to death with conventional therapies, metabolically adapted to low levels of oxygen and nutrients,” Zerrouqi says. “At this stage, the tumor seems to have a clear deadly intent.”

A fragment of one of the proteins that cancer cells use to exert the clotting effect, called TFPI2, could be used to antagonize blood clotting  therapeutically, they write in Cancer Research. The findings could also have implications for understanding the effects of current medications, such as the angiogenesis inhibitor bevacizumab, also known as Avastin.

*A paper by Van Meir and Dan Brat from 2005 is the top Google link under the search term “glioblastoma clotting.”

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