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News Article | May 25, 2017
Site: www.sciencedaily.com

Every cell in our body runs like a tiny factory that makes specialized products, using the carefully guarded instructions kept in the CEO's office. But every once in a while, an invader tries to get inside and hijack the whole works, through a combination of industrial espionage and hostile takeover. If it succeeds in getting into the CEO's office -- the nucleus, where the DNA plans are kept -- things never end well for the original factory. Scientists still don't know how viruses accomplish this feat without getting caught by the factory security guards. But new research from the University of Michigan reveals important clues about one of the most mysterious types, called polyomaviruses. The findings could aid the search for new treatments or preventive strategies against the problems that polyomaviruses can cause, including the deadly skin cancer called Merkel cell carcinoma, and fatal problems in people who have weak immune systems from organ transplants and cancer treatment. Publishing in Nature Communications, a U-M team reports their findings about a kind of factory takeover that actually fools the cell into building the very doorway that can let polyomavirus get close to the CEO's office. A few more steps, and it can take over the whole factory. "Our results suggest polyomavirus hijacks a kind of cellular molecular motor whose normal job is to transport cargoes, and uses it to build a penetration site or portal," says Billy Tsai, Ph.D., the U-M Medical School Department of Cell and Developmental Biology who worked with postdoctoral fellow Madhu Sudhan Ravindran, Ph.D. and others to make the discovery. That kind of motor -- called kinesin-1 -- acts like an army of forklifts in the factory. Each kinesin-1 molecule travels along tiny stiff paths called microtubules, to bring loads of proteins where they need to go inside the cell in order to build products. But according to the team's new findings, each polyomavirus particle tricks some of these forklifts into bringing just what the virus needs to build its own door. Once built, that door leads into the waiting room just outside the CEO's office -- the area inside the cell nearest the nucleus. "From the cell's point of view it's a mild process," adds Ravindran. "Only a few virus particles end up being successful -- but once they are, they can reach the nucleus, letting a while gang of thieves loose." Scientists around the world have studied polyomavirus for decades, but none has been able to figure out how it achieves this key step -- until now. Could the new findings help lead to better prevention or treatment against Merkel cell cancer, or other polyomavirus diseases that affect organ transplant recipients, HIV/AIDS patients, and cancer survivors? It's too early to say, says Tsai, who is the Corydon Ford Collegiate Professor and a member of U-M's Biological Sciences Scholars Program. But he notes that some drug companies are already creating medications that aim to block other cellular motors and keep cancer cells from dividing. More about the study To do the research, Tsai and Ravindran teamed up with Kristen Verhey, Ph.D., the interim chair of Cell and Developmental Biology at U-M, and her postdoctoral fellow Martin Engelke, Ph.D. They have developed specialized tools that allow researchers to see activity along the microtubules and other structural "skeleton" elements inside cells. The team used a polyomavirus that infects monkeys but not people -- called SV40 -- and looked at how it interacted with the membrane that encloses the endoplasmic reticulum, or ER. If a cell is a factory, and the nucleus is the boss's office with the "blueprints" for the products the factory makes, then the ER is the factory floor. It's where the orders from management get processed, and where products get made from raw materials and packaged up to go to their next step. Scientists already knew that polyomaviruses enter our cells by picking a lock in the factory wall -- and riding in a shipping container called a endosome straight to the ER. It's as if they hopped in a mail cart and rode it straight to the factory floor. But once in the ER, the viruses seem trapped. Unlike some types of virus, polyomaviruses don't have a membrane surrounding their hard inner shell -- one that can bind with the ER membrane and let them escape. The new research shows how they achieve this feat instead: by binding to a protein in the ER membrane, and using it to summon the kinesin-1 forklifts and certain supplies that they can carry. If enough virus particles get this to happen in a certain area, they can create a site where the ER membrane can be penetrated -- what the U-M researchers have dubbed a "focus." While many kinesin molecules travel along straight microtubules that head from the ER to the outer edges of cells, the researchers also show that kinesin-1 especially likes to travel along microtubules that bend and curve to stay near the nucleus. That makes it ideal for constructing that "focus" point and allowing the virus to escape the ER into the space near the nucleus. Polyomaviruses aren't the only viruses that lack an envelope, or membrane, that could make it easier for them to bind with our cells' own outer and ER membranes. Papillomavirus -- which causes many cases of cervical cancer -- and polio virus are among other non-enveloped viruses that also have to figure out a way to breach both cell and ER membranes. The viruses are too big to use existing openings. So the new research may aid understanding of them too. The exact way they summon those forklifts still isn't clear, but Tsai and Ravindran are working on finding it. They're also looking at how the polyomavirus that has succeeded in getting out of the ER membrane manages to infiltrate the CEO's office -- the nucleus -- and inject its own genetic material. That allows the virus to hijack the factory to make copies of itself, and then self-destruct to send those new viruses into the body. "Only a few particles end up being successful, with only one to two percent reaching their final destination," Tsai notes. "They have to be able to do that without destroying the normal function of kinesin-1. Now that we understand this, our goal should be finding a way to destroy this specific kind of motor activity without harming the infected cell."


But every once in a while, an invader tries to get inside and hijack the whole works, through a combination of industrial espionage and hostile takeover. If it succeeds in getting into the CEO's office - the nucleus, where the DNA plans are kept—things never end well for the original factory. Scientists still don't know how viruses accomplish this feat without getting caught by the factory security guards. But new research from the University of Michigan reveals important clues about one of the most mysterious types, called polyomaviruses. The findings could aid the search for new treatments or preventive strategies against the problems that polyomaviruses can cause, including the deadly skin cancer called Merkel cell carcinoma, and fatal problems in people who have weak immune systems from organ transplants and cancer treatment. Publishing in Nature Communications, a U-M team reports their findings about a kind of factory takeover that actually fools the cell into building the very doorway that can let polyomavirus get close to the CEO's office. A few more steps, and it can take over the whole factory. "Our results suggest polyomavirus hijacks a kind of cellular molecular motor whose normal job is to transport cargoes, and uses it to build a penetration site or portal," says Billy Tsai, Ph.D., the U-M Medical School Department of Cell and Developmental Biology who worked with postdoctoral fellow Madhu Sudhan Ravindran, Ph.D. and others to make the discovery. That kind of motor - called kinesin-1 - acts like an army of forklifts in the factory. Each kinesin-1 molecule travels along tiny stiff paths called microtubules, to bring loads of proteins where they need to go inside the cell in order to build products. But according to the team's new findings, each polyomavirus particle tricks some of these forklifts into bringing just what the virus needs to build its own door. Once built, that door leads into the waiting room just outside the CEO's office - the area inside the cell nearest the nucleus. "From the cell's point of view it's a mild process," adds Ravindran. "Only a few virus particles end up being successful - but once they are, they can reach the nucleus, letting a while gang of thieves loose." Scientists around the world have studied polyomavirus for decades, but none has been able to figure out how it achieves this key step - until now. Could the new findings help lead to better prevention or treatment against Merkel cell cancer, or other polyomavirus diseases that affect organ transplant recipients, HIV/AIDS patients, and cancer survivors? It's too early to say, says Tsai, who is the Corydon Ford Collegiate Professor and a member of U-M's Biological Sciences Scholars Program. But he notes that some drug companies are already creating medications that aim to block other cellular motors and keep cancer cells from dividing. More about the study To do the research, Tsai and Ravindran teamed up with Kristen Verhey, Ph.D., the interim chair of Cell and Developmental Biology at U-M, and her postdoctoral fellow Martin Engelke, Ph.D. They have developed specialized tools that allow researchers to see activity along the microtubules and other structural "skeleton" elements inside cells. The team used a polyomavirus that infects monkeys but not people - called SV40 - and looked at how it interacted with the membrane that encloses the endoplasmic reticulum, or ER. If a cell is a factory, and the nucleus is the boss's office with the "blueprints" for the products the factory makes, then the ER is the factory floor. It's where the orders from management get processed, and where products get made from raw materials and packaged up to go to their next step. Scientists already knew that polyomaviruses enter our cells by picking a lock in the factory wall - and riding in a shipping container called a endosome straight to the ER. It's as if they hopped in a mail cart and rode it straight to the factory floor. But once in the ER, the viruses seem trapped. Unlike some types of virus, polyomaviruses don't have a membrane surrounding their hard inner shell - one that can bind with the ER membrane and let them escape. The new research shows how they achieve this feat instead: by binding to a protein in the ER membrane, and using it to summon the kinesin-1 forklifts and certain supplies that they can carry. If enough virus particles get this to happen in a certain area, they can create a site where the ER membrane can be penetrated - what the U-M researchers have dubbed a "focus". While many kinesin molecules travel along straight microtubules that head from the ER to the outer edges of cells, the researchers also show that kinesin-1 especially likes to travel along microtubules that bend and curve to stay near the nucleus. That makes it ideal for constructing that "focus" point and allowing the virus to escape the ER into the space near the nucleus. Polyomaviruses aren't the only viruses that lack an envelope, or membrane, that could make it easier for them to bind with our cells' own outer and ER membranes. Papillomavirus - which causes many cases of cervical cancer - and polio virus are among other non-enveloped viruses that also have to figure out a way to breach both cell and ER membranes. The viruses are too big to use existing openings. So the new research may aid understanding of them too. The exact way they summon those forklifts still isn't clear, but Tsai and Ravindran are working on finding it. They're also looking at how the polyomavirus that has succeeded in getting out of the ER membrane manages to infiltrate the CEO's office - the nucleus - and inject its own genetic material. That allows the virus to hijack the factory to make copies of itself, and then self-destruct to send those new viruses into the body. "Only a few particles end up being successful, with only one to two percent reaching their final destination," Tsai notes. "They have to be able to do that without destroying the normal function of kinesin-1. Now that we understand this, our goal should be finding a way to destroy this specific kind of motor activity without harming the infected cell." Explore further: Understanding the role of human polyomaviruses in cancer


Virus harnesses cellular 'motors' to bring together the supplies that can build a portal for itself ANN ARBOR, Mich. -- Every cell in our body runs like a tiny factory that makes specialized products, using the carefully guarded instructions kept in the CEO's office. But every once in a while, an invader tries to get inside and hijack the whole works, through a combination of industrial espionage and hostile takeover. If it succeeds in getting into the CEO's office - the nucleus, where the DNA plans are kept -- things never end well for the original factory. Scientists still don't know how viruses accomplish this feat without getting caught by the factory security guards. But new research from the University of Michigan reveals important clues about one of the most mysterious types, called polyomaviruses. The findings could aid the search for new treatments or preventive strategies against the problems that polyomaviruses can cause, including the deadly skin cancer called Merkel cell carcinoma, and fatal problems in people who have weak immune systems from organ transplants and cancer treatment. Publishing in Nature Communications, a U-M team reports their findings about a kind of factory takeover that actually fools the cell into building the very doorway that can let polyomavirus get close to the CEO's office. A few more steps, and it can take over the whole factory. "Our results suggest polyomavirus hijacks a kind of cellular molecular motor whose normal job is to transport cargoes, and uses it to build a penetration site or portal," says Billy Tsai, Ph.D., the U-M Medical School Department of Cell and Developmental Biology who worked with postdoctoral fellow Madhu Sudhan Ravindran, Ph.D. and others to make the discovery. That kind of motor - called kinesin-1 - acts like an army of forklifts in the factory. Each kinesin-1 molecule travels along tiny stiff paths called microtubules, to bring loads of proteins where they need to go inside the cell in order to build products. But according to the team's new findings, each polyomavirus particle tricks some of these forklifts into bringing just what the virus needs to build its own door. Once built, that door leads into the waiting room just outside the CEO's office - the area inside the cell nearest the nucleus. "From the cell's point of view it's a mild process," adds Ravindran. "Only a few virus particles end up being successful - but once they are, they can reach the nucleus, letting a while gang of thieves loose." Scientists around the world have studied polyomavirus for decades, but none has been able to figure out how it achieves this key step - until now. Could the new findings help lead to better prevention or treatment against Merkel cell cancer, or other polyomavirus diseases that affect organ transplant recipients, HIV/AIDS patients, and cancer survivors? It's too early to say, says Tsai, who is the Corydon Ford Collegiate Professor and a member of U-M's Biological Sciences Scholars Program. But he notes that some drug companies are already creating medications that aim to block other cellular motors and keep cancer cells from dividing. To do the research, Tsai and Ravindran teamed up with Kristen Verhey, Ph.D., the interim chair of Cell and Developmental Biology at U-M, and her postdoctoral fellow Martin Engelke, Ph.D. They have developed specialized tools that allow researchers to see activity along the microtubules and other structural "skeleton" elements inside cells. The team used a polyomavirus that infects monkeys but not people - called SV40 - and looked at how it interacted with the membrane that encloses the endoplasmic reticulum, or ER. If a cell is a factory, and the nucleus is the boss's office with the "blueprints" for the products the factory makes, then the ER is the factory floor. It's where the orders from management get processed, and where products get made from raw materials and packaged up to go to their next step. Scientists already knew that polyomaviruses enter our cells by picking a lock in the factory wall - and riding in a shipping container called a endosome straight to the ER. It's as if they hopped in a mail cart and rode it straight to the factory floor. But once in the ER, the viruses seem trapped. Unlike some types of virus, polyomaviruses don't have a membrane surrounding their hard inner shell - one that can bind with the ER membrane and let them escape. The new research shows how they achieve this feat instead: by binding to a protein in the ER membrane, and using it to summon the kinesin-1 forklifts and certain supplies that they can carry. If enough virus particles get this to happen in a certain area, they can create a site where the ER membrane can be penetrated - what the U-M researchers have dubbed a "focus". While many kinesin molecules travel along straight microtubules that head from the ER to the outer edges of cells, the researchers also show that kinesin-1 especially likes to travel along microtubules that bend and curve to stay near the nucleus. That makes it ideal for constructing that "focus" point and allowing the virus to escape the ER into the space near the nucleus. Polyomaviruses aren't the only viruses that lack an envelope, or membrane, that could make it easier for them to bind with our cells' own outer and ER membranes. Papillomavirus - which causes many cases of cervical cancer - and polio virus are among other non-enveloped viruses that also have to figure out a way to breach both cell and ER membranes. The viruses are too big to use existing openings. So the new research may aid understanding of them too. The exact way they summon those forklifts still isn't clear, but Tsai and Ravindran are working on finding it. They're also looking at how the polyomavirus that has succeeded in getting out of the ER membrane manages to infiltrate the CEO's office - the nucleus - and inject its own genetic material. That allows the virus to hijack the factory to make copies of itself, and then self-destruct to send those new viruses into the body. "Only a few particles end up being successful, with only one to two percent reaching their final destination," Tsai notes. "They have to be able to do that without destroying the normal function of kinesin-1. Now that we understand this, our goal should be finding a way to destroy this specific kind of motor activity without harming the infected cell." The research was funded by the National Institutes of Health (GM113722, AI064296) and also received support from the U-M Medical School's Protein Folding Diseases Initiative.


News Article | February 23, 2017
Site: www.sciencenews.org

Like many living things, a cancer cell cannot survive without oxygen. When young and tiny, a malignancy nestles inside a bed of blood vessels that keep it fed. As the mass grows, however, its demand for oxygen outpaces supply. Pockets within the tumor become deprived and send emergency signals for new vessel growth, a process called angiogenesis. In the 1990s, a popular cancer-fighting theory proposed interfering with angiogenesis to starve tumors to death. One magazine writer in 2000 called the strategy “the most important single insight about cancer of the past 50 years.” It made such intuitive sense. Rakesh Jain viewed angiogenesis through a different lens. Trained as an engineer, not a biologist, Jain was studying tumor vasculature during the height of excitement about drugs that could impede vessel growth. He was bothered by the fact that capillaries that arise in the tumor aren’t normal; they’re gnarled and porous, incapable of effective blood flow in the same way a leaky pipe is lousy at delivering water. The expanding tumor squeezes smaller vessels, making them even less able to transport blood. “The mantra was, ‘Let’s starve tumors,’ ” recalls Jain, director of the Edwin L. Steele Laboratories for Tumor Biology at Harvard Medical School. “I said, ‘No, we need to do the opposite.’ ” In 2001, he published a commentary in Nature Medicine predicting that angiogenesis inhibitors would not entirely shrivel the tumor. Instead, he argued, starving tumors might make them harder to treat. “I was sticking my neck out and saying this is not a good thing to do,” he says. “I had tremendous resistance.” Time has proved him right. Once they came on the market, anti-angiogenesis drugs were not the boon doctors had hoped for. Most disturbing, some patients saw their tumors shrink, only to have the disease return with renewed vengeance. Today, more than a decade after the introduction of the first tumor-starving drug, researchers have a far greater understanding of the role of oxygen deprivation in cancer. Instead of slowing tumors, hypoxia appears to trigger a metabolic panic that can drive growth, drug resistance and metastasis. Rescue proteins called hypoxia-inducible factors, or HIFs, open a bag of tricks so tumors can adapt and outrun the body’s defenses. But there’s now reason for hope: Recent insights into the effects of oxygen deprivation in cancer are sparking new ideas and providing the blueprint for treatments that could short-circuit a cancer’s ability to survive and spread, and help make existing drugs more effective. While the idea of starving cancer made sense, the approach may have underestimated the strength and complexity of a tumor’s resilience. Since oxygen is essential for so much of life, nature equips cells with elaborate safeguards that kick in when the oxygen-rich blood supply dwindles — whether the cells are part of a tumor or part of a muscle straining for one last push of strength. When oxygen levels drop, newly minted proteins stampede throughout the cell, turning on a frenzy of chemical reactions that offer protection from the crisis. Cancer cells distort this natural coping mechanism for their own means. Growing new vessels is just one move in an elaborate strategy. Many changes accompany hypoxia, including: The malignant cells loosen from each other and become less adhesive, ready to break free; tendrils of collagen, a natural binding substance, form and start to reach out to nearby vessels; and proteins appear on the cell surface to pump out lactic acid, a product of the tumor’s switch from primarily aerobic to anaerobic respiration. Researchers now think stopping enough of these and other changes could cripple the cancer. Much of the research focuses on the proteins that are among the first to deploy when a cell senses a danger of asphyxiation. “At zero oxygen, the cell can’t survive,” says Daniele Gilkes of Johns Hopkins University School of Medicine. “Inside a tumor you will see these regions of necrosis,” or dead cells. But those cells that are low on oxygen but still alive will produce new proteins: Key among them are HIF-1 and HIF-2. Both are transcription factors — they help transcribe DNA instructions into RNA. Under normal conditions, the genes that make HIF proteins are mostly silent. Once HIF proteins are made, they turn on genes — Gilkes estimates there are hundreds — that enable cells to live when oxygen concentrations are low. Gilkes’ target of choice is HIF-1. It is not only a first responder, but the protein also appears to be key to cancer’s spread. Tumors with high levels of HIF-1, particularly when concentrated at the invasive outer edge of the mass, are more likely to become metastatic, invading other parts of the body. The reverse is also true: Human tumors transplanted into mice that genetically can’t produce HIF-1 are less likely to spread. The reasons are complicated, Gilkes says, but she considers one thing really interesting: HIF-1 is involved with a lot of enzymes in collagen formation. The collagen appears to provide a means of escape. Last year, in a review in the International Journal of Molecular Sciences, Gilkes described genes, found by her lab group and others, that breast tumors activate to degrade the surrounding environment. In turn, the tumor wraps itself in a stringy web of collagen. As the collagen forms, the strands stretch outward from the tumor and latch onto nearby vessels. “We think cancer cells will find this collagen and use it to migrate and glide.” She calls them “collagen highways.” Her laboratory captured video of human tumor cells migrating along a fibrous strand. “To see them move is really scary.” Once they’ve broken from their home tumor, many types of cancer, including prostate and breast cancers, commonly move into bones. This is no coincidence, Gilkes says. Bones lack the dense thickets of blood vessels that run through soft tissues. That means cancer cells migrating from a hypoxic environment, and therefore already trained for low oxygen, would find hospitable surroundings in the bone. Her lab group is now looking for ways to block collagen formation to close the travel lanes and perhaps keep the cancer from spreading. She and others are also working to find a way to inhibit HIF-1 directly, but so far those efforts have proved challenging. HIF-1’s accomplice, HIF-2, may be a more available target. HIF-2 is a molecule made of two parts that clamp onto DNA to trigger production of other proteins that make tumors tougher to kill. In 2009, structural biologists at University of Texas Southwestern Medical Center in Dallas discovered that the HIF-2 protein had a large cavity. “Usually proteins don’t have holes inside them,” says James Brugarolas, leader of UT Southwestern’s kidney cancer program. With the discovery, researchers began working on a way to use the gap as a foothold for drugs. Now in development, the experimental drug PT2399 slips inside HIF-2 and effectively breaks the molecule in two. Brugarolas and colleagues from six other institutions and the biotech company Peloton Therapeutics Inc. in Dallas published results of the first animal tests of the compound in Nature in November. In mice with implanted grafts of human kidney tumors, PT2399 split HIF-2 and slowed growth in 56 percent of tumors — better than a standard treatment. Brugarolas hypothesizes that the drug worked only about half the time because the other half of tumors relied more heavily on HIF-1. A similar HIF-2–busting drug is now in Phase I safety testing in humans, described in June in Chicago at the annual meeting of the American Society of Clinical Oncology. While Phase I studies are not designed to test whether the treatment works, the drug showed few side effects among 51 people with advanced kidney cancer who took the drug at ever-increasing doses. The patients had already been through multiple types of treatments, one as many as seven. After taking the drug, 16 patients experienced a slowing in disease progression, three more had a partial response and one a complete reversal. Given the dearth of treatments for advanced kidney cancer, Brugarolas says, “this is a big deal.” Still more molecules throw a lifeline to hypoxic tumors in ways that scientists are just beginning to understand. In 2008, pathologist David Cheresh and colleagues at the University of California, San Diego announced a curious discovery in Nature: Depriving cells of vascular endothelial growth factor, or VEGF — the key protein responsible for new vessel growth in a tumor and the main target of drugs that block angiogenesis — could actually make tumors more aggressive. His team went on to discover the same was true for another popular class of drugs, which work by depriving a tumor cell of nutrients in the same way anti-angiogenesis drugs limit oxygen. The drugs, called EGFR inhibitors, were capable of doing the opposite of what was expected: They could make tumors stronger. Cheresh believes that hypoxia — and other stresses of low blood supply, like nutrient deprivation — inflict a wound on the tumor. When normal tissues sustain an injury (like a cut), they immediately enter a period of healing and regeneration. The bleeding stops and the skin grows back. Low oxygen delivers a blow to tumor cells, sending them into a similar state of rejuvenation, he says. “They’re now prepared to survive not only the hypoxia, but everything else thrown at it.” In 2014, Cheresh published his take on why this occurs, at least in some cases, in Nature Cell Biology. He and his team described a molecule called avb3 found on the surface of drug-resistant tumors that appears to reprogram tumor cells into a stem cell–like state. As embers of the original tumor that are often impermeable to treatment, these stem cell–like cells can lie quietly for a time and then reignite. The discovery of avb3 has redefined how Cheresh thinks about resistance. He no longer believes that tumors defy chemotherapy in the way bacteria overcome antibiotics, with only the strongest cells surviving and then roaring back to become dominant. “The tumor cells are adapting, changing in real time,” Cheresh says. In short, his data suggest that when EGFR inhibitors deprive a cell of nutrients, some cells survive not because they are naturally tougher, but because the appearance of avb3 transforms them into drug-resistant stem cells. The good news is that laboratory tests suggest an experimental drug might block this reprogramming, and it may even prevent chemotherapy resistance. A clinical trial will soon begin that combines usual cancer treatment with this avb3-disabling drug, in a one-two punch aimed at reversing or delaying resistance so the treatment can do its job. There are still more ways tumors withstand low oxygen. They start eating leftovers. HIF-1 triggers a switch from oxygen-based aerobic respiration to anaerobic respiration using pyruvate, a product of glucose breaking down. The strategy works in the short term; it’s the reason your muscles keep pumping for a time, even when you’re gasping for air on the last few yards of a sprint. Problem is, anaerobic respiration leaves a trail of lactic acid. A lot of it. “Lactic acid buildup leads to a precipitous drop in pH inside of the tumor,” says Shoukat Dedhar of the BC Cancer Research Centre in Vancouver. To compensate, HIF-1 deploys a fleet of proteins that remove the acid so it won’t accumulate and burn up the cell. Dedhar’s laboratory didn’t start out studying hypoxia. “We had tumors that were readily metastatic and genetically related tumors that couldn’t metastasize,” he says. Those tumors that easily spread were producing HIF-1, along with products from other genes. Searching for the functions of those genes, his group and others found two proteins important in pH balance. The first, MCT-4, acts like a molecular sump pump, bailing out lactic acid. But it’s not enough to normalize the pH, Dedhar says. That job goes to the second protein, carbonic anhydrase 9, or CAIX. “Its job is simply to convert carbon dioxide to bicarbonate, which then neutralizes the acid,” he says. In March 2016, in a review in Frontiers in Cell and Developmental Biology, Dedhar and colleagues described how to improve cancer treatment by taking away some of the tools for hypoxia survival — that is, keeping the cell from neutralizing acid — while simultaneously giving drugs that boost the immune system. His team has developed new compounds that specifically block CAIX. Since CAIX is almost exclusively produced in tumor cells, CAIX inhibitors should theoretically have few side effects. A Phase I safety trial is testing possible drugs now. Harvard’s Jain is still making the case for bathing the tumors in oxygen, giving them more blood, not less. This could keep the tumor from becoming hypoxic and throwing up a new series of defenses, including a flood of angiogenesis-promoting proteins, which produce tormented circulation. When he proposed that concept in 2001, “I thought abnormal vessels were bad,” he says. “I now think they are worse.” His idea is to make tumor vasculature more normal, using the very drugs that he was concerned about almost two decades ago. His research suggests that giving anti-angiogenesis drugs in modest doses will keep the vessels from becoming abnormal, making them less tortured and more capable of normal blood flow (SN: 10/5/13, p. 20). He believes the restored oxygen not only shuts down the hypoxic response that gives the cancer a survival advantage, but also serves as a conduit for chemotherapy drugs and immune cells to penetrate deeper into the tumor. Oxygen is also necessary for radiation to work. His latest experiments take the concept of more oxygen, not less, even further. He combined two chemotherapy drugs with losartan, a generic medicine used to control blood pressure. The result, reported in Nature Communications in 2013, was a delay in pancreatic and breast tumor growth in mice. Another experiment from Jain and colleagues, published in 2016 in Translational Oncology, had similar results. “We are finding every therapy works better when we do this,” he says. A clinical trial is now under way at Massachusetts General Hospital testing whether giving losartan during radiation and chemotherapy will improve results for pancreatic cancer patients. The concept still remains unproven, but Jain has reason for optimism. And he is no longer in the scientific minority. Last May, he received the National Medal of Science from President Barack Obama, who commended Jain for “groundbreaking discoveries of principles leading to the development and novel use of drugs for treatment of cancer.” Jain hopes to see the day, not long in the future, when hypoxic tumors are defeated by giving them the very thing they need the most. This article appears in the March 4, 2017, issue of Science News with the headline, "Deflating cancer: New approaches to low oxygen may thwart tumors."


A team of researchers from the Perelman School of Medicine at the University of Pennsylvania have shed new light on how the structure of regulatory sequences in DNA is packaged in a cell. "This work has implications for better understanding the role that gene sequences called enhancers play within our DNA for governing gene activity," said senior author Ken Zaret, PhD, a professor of Cell and Developmental Biology and director of the Institute for Regenerative Medicine. The findings are published this week in Molecular Cell.


News Article | December 16, 2016
Site: phys.org

The new study, performed at the University of Michigan and reported in Nature Materials, provides the first opportunity to study the development of amnion, an essential tissue that envelops and protects the growing fetus. The method could lead to a more complete understanding of early human development and the mechanisms behind infertility and early pregnancy loss. It could also enable the production of better wound dressings. "People have a fairly good understanding of what happens in embryos before and after implantation," said Jianping Fu, U-M associate professor of mechanical engineering. "But what is happening during implantation, including the process of amnion development, is a black box." While it is relatively easy for scientists to mimic the free-floating phase of an embryo's development in the lab, roughly one week after conception, modeling implantation into the womb has been impossible. Now, a team led by Fu and Deborah Gumucio, the James Douglas Engel Collegiate Professor of Cell and Developmental Biology at the U-M Medical School, has emulated this process with both human embryonic stem cells and adult cells reprogrammed into stem cells. "This research is about the amnion, which is actually an extraembryonic tissue necessary for survival of the embryo itself," Gumucio said. "It is extremely exciting since amnion has never before been generated in a dish." Gumucio added that many pregnancies are lost even before women know they're pregnant. Failure to implant and the lack of peripheral tissues like amnion are among the causes of such pregnancy losses. Doctors and researchers are very interested in finding ways to diagnose and treat these problems. Previously, Gumucio's group showed that embryonic stem cells have a strong tendency to form a hollow sphere, structurally similar to the precursor of amnion tissue. Gumucio and Fu teamed up to explore whether the initiating signal for embryonic stem cells to form amnion tissue might be mechanical in nature. The team tested different methods to produce amnion. One worked: a thick, soft bed of gel, covered with a looser gel, which Gumucio compared to a bed of fully congealed Jello with a layer of partially set Jello on top. In this structure, the stem cells began to turn into amnion cells, organized in a shell around an empty cavity. By contrast, on a thin bed, which the cells perceive as having less give, the stem cells stayed stem cells. In other words, for cells to begin to form amnion, they need to sense that they have landed on a suitable surface—what scientists term a mechanical signal. To confirm that the trigger for embryonic stem cells to form amnion is mechanical, the team made two different cell culture plates covered in microscopic silicone bristles, again with the loose gel on top. On the longer bristles, which felt more like a soft thick gel bed to the cells, the stem cells turned into amnion. On the short bristles, which felt stiffer, the cells remained stem cells. "This is groundbreaking," Fu said. "Our method provides significant opportunity for developmental biologists to extend their research into a window of human development that was previously inaccessible to study." The researchers first did the work with human embryonic stem cells obtained from WiCell or derived at the Medical School's MStem Cell laboratory in accordance with U.S. law, using private funding and donated embryos left over from fertility treatments. Then, they were able to show that reprogrammed adult skin cells, known as induced pluripotent stem cells, can also be made to mimic amnion growth. Gumucio notes that the method could one day be relevant to fertility medicine. If the research continues to show promise, it's theoretically possible that skin biopsies from infertile couples could be cultured to reveal potential genetic problems affecting amnion development. It could also pave the way for the standardized production of amnion. Amnion is used to dress large wounds such as serious burns because it reduces inflammation and forms a strong, flexible covering to protect them as they heal. Amnion dressings are currently made from amniotic tissue discarded after babies are born, but a purpose-made amnion product could avoid problems such as genetic incompatibility between donor and recipient or the transmission of diseases. The study is titled, "Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche." The human embryonic stem cells were provided by WiCell and the privately funded U-M MStem Cell Laboratories, which store and grow stem cell lines from donated embryos. All cells used were from lines that have been officially registered with the National Institutes of Health, certified for research under U.S. law. Explore further: Stem cells derived from amniotic tissues have immunosuppressive properties More information: Yue Shao et al. Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche, Nature Materials (2016). DOI: 10.1038/nmat4829


News Article | October 27, 2016
Site: www.scientificamerican.com

The disappearance of snakes’ limbs is more than a story of loss—it is a complex history detailed in their DNA. Hoping to understand how and why evolution shaped the snake as it did—and what happened to its genome when it stopped walking—a team of scientists is using the gene-editing CRISPR/Cas9 system to produce the same change in mice. Advances in genetic technology have accelerated the study of evolution via genomics, says Axel Visel, a geneticist at the Lawrence Berkeley National Laboratory. His team hopes to better understand the evolution of morphology, or the way animals physically look. “We decided to look at one of the most dramatic morphological adaptations that happened in vertebrate evolution,” he says: “The loss of limbs in snakes as they evolved from an ancestor that looked like lizards.” His team took advantage of prior work sequencing the genomes of several snake species including boas, pythons and cobras. Snake genomes, like those of humans, have so-called enhancer sequences that regulate how other sequences should function. Visel’s team found that one enhancer called the zone of polarizing activity regulatory sequence, or ZRS, had degraded in snake species; some of the protein-making instructions in the snake ZRS looked like they had been copied so many times that numerous imperfections had appeared, changing some of the DNA’s base pairs (sets of molecules that determine the genetic instructions). ZRS happens to enhance the sonic hedgehog gene, which is in charge of creating a protein crucial to embryonic limb development. In the latest research the scientists first swapped out the mouse ZRS from mouse embryos using a more common genetic replacement methods. They replaced the sequence with ZRS specific to different animals including horses, humans and snakes, combined with a special gene that would cause the tips of a mouse embryo’s developing limbs to turn blue after chemical treatment if the new ZRS was doing its job. When the researchers looked at the animal embryos the tips of all of the mice’s limbs had turned blue—except for those with snake ZRS, where either nothing happened or the ZRS seemed to behave in a way that did not imply limb development. Essentially, snake ZRS did not seem to be doing its job. This was made vividly clear when Visel’s team used CRISPR to create live mice with their ZRS swapped with that of snakes. The “serpentized” mice had severely underdeveloped limbs; their lower arms and legs were each serverely reduced—in most cases to stunted bone. But the mouse limbs formed normally when the team replaced the enhancer with human or even fish DNA. Visel’s team released its results in Cell last week. Visel emphasized that his team has not discovered how snakes’ limbs disappeared. Rather, they concluded that once snakes’ limbs were gone, evolution did not require the ZRS to actually work. A mutation in a snake’s ZRS would not have harmed snakes as they evolved—because they do not use their legs. Working separately, another team happened upon complementary results when looking at limbs in python embryos. This study’s authors said they found that python embryos still develop cartilage precursors to all of the parts of a leg—but the snake’s body sheds the lower leg cartilage and keeps just a rudimentary leg bone. That is probably because the ZRS degraded while another important set of limb enhancers stuck around. These enhance HOXD. (short for Homeobox-D, the proteins they code for) the same way that ZRS enhances sonic hedgehog. HOXD regulate legs and genitalia simultaneously, so evolution maintained its enhancers in order for snakes to be able to keep mating, says Martin Cohn, professor at the University of Florida. He and his co-author recently published their results in Current Biology. Biologists have experimented with enhancers and their effects on limb development in mice as early as 2005, says Kimberly Cooper, assistant professor in Cell and Developmental Biology at the University of California, San Diego. Cooper was not involved in the new study, but notes that Visel’s use of CRISPR technology allowed for far cheaper and faster gene replacement in mice. “It’s really exciting,” Cooper says. “The end result of this engineering is no different than stuff we’ve done before. But we’ve made it so much more technologically simple.” Lawrence Berkeley National Laboratory’s Animal Welfare and Research Committee reviewed and approved the animal use protocol for the latest study, says Antoine Snijders, the committee chair. “All the work described in the protocol is what the principal investigator is allowed to perform.” Although deliberately producing limbless mice might sound macabre, the work is ethically justifiable in this case, says Carolyn Neuhaus, postdoctoral fellow at New York University School of Medicine’s Division of Medical Ethics, who was not involved in the study. “Refining a technique and using a new technology is an important contribution to science and publicly valuable,” she says. Visel adds that there is no alternative to altering mice genes in these kinds of studies. “There’s no way you can do these kinds of experiments in computation models and be confident with the results,” he says. Using CRISPR in animal experiments will hopefully lead to productive debates regarding the gene-editing technology in general, says Arthur Caplan, N.Y.U. bioethicist. Caplan believes such a dialogue is especially important in the context of eventually using the technique in medicine. “I think it’s really fascinating that most of the ethical attention is focused on what gene editing means to humans,” he says. “You want to debate CRISPR use at the level of mice, not men, first.” Visel does not feel his work has a place in such a debate, and expects the field will see more studies using CRISPR to understand limb development. “These kind of studies were possible before, but now they’re within reach for many of these experiments in a more targeted way,” Visel says. “That excites me scientifically.”


Much like its free-living relatives, the flatworm Schistosoma mansoni has a population of stem cells known as neoblasts that are capable of self-renewal, but the function of these cells was previously unknown. Now, in a study to be published in the journal eLife, researchers have found that the neoblasts are destined to become cells that generate and regenerate the worm's outer layer of skin, a unique tissue called the tegument. "The tegument serves as a barrier between S. mansoni and the bloodstream of its host, which would otherwise be an inhospitable environment for the parasite," says first author James Collins, Assistant Professor of Pharmacology at the UT Southwestern Medical Center. "This tissue has long been considered an evolutionary innovation for parasitic flatworms to evade their host's immune defenses. Our current findings suggest that stem cells are playing a key role in perpetually renewing it, and we believe this is important for the parasite's ability to survive for decades inside their human host." Schistosomes cause the disease schistosomiasis, the symptoms of which result from the worms' eggs becoming lodged in host tissues, such as the liver and bladder, evoking the immune system's response. People become infected with the parasites when they are exposed to larvae carried by freshwater snails in the water where they bathe, swim, fish, wash clothes or water their livestock. Schistosomiasis is among the world's deadliest neglected tropical diseases, killing an estimated 280,000 people annually, around 90% of them in Africa. The chronic symptoms of infection deprive millions more of the chance to live healthy and productive lives, effectively condemning them to a life of poverty. One of the first signs of infection is an itchy rash where larvae penetrate the skin, followed by blood in the urine or faeces. Twenty million schistosomiasis sufferers develop painful, severe and sometimes disfiguring disabilities due to complications, including damage to the kidneys or liver and bladder cancer. Larvae can migrate to the heart and enter the lungs. Children can develop anaemia, malnutrition, and learning disabilities. To discover the skin-reviving function of schistosome neoblasts, the researchers compared the short and long-term consequences of reducing the number of neoblasts in the parasites. "Our experiments showed that the cells from which the tegument originates are short-lived and rapidly renewed, relying on a pool of stem cells for their continuous renewal," explains senior author Phillip Newmark, Howard Hughes Medical Institute Investigator and Professor of Cell and Developmental Biology at the University of Illinois at Urbana-Champaign. "Within a week after reducing these stem cells with irradiation, nearly all the cells destined to contribute to the tegument had been depleted." Neglected tropical diseases are among the most common afflictions of humankind and are so-called because they persist exclusively in the poorest communities. They thrive in places with unsafe water, poor sanitation, and limited access to basic healthcare. The researchers believe it is now essential to determine whether disrupting the stem cells of schistosomes, and their ability to generate new tegumental cells, will have any effect on the parasites inside their human host. This could provide insights for potential new ways to break down the barrier with the immune system, allowing it to kill the worms. Explore further: Stash of stem cells found in a human parasite More information: James J Collins et al. Stem cell progeny contribute to the schistosome host-parasite interface, eLife (2016). DOI: 10.7554/eLife.12473


News Article | February 15, 2017
Site: www.eurekalert.org

A puzzling question has lurked behind SMA (spinal muscular atrophy), the leading genetic cause of death in infants. The disorder leads to reduced levels of the SMN protein, which is thought to be involved in processing RNA, something that occurs in every cell in the body. So why does interfering with a process that happens everywhere affect motor neurons first? Scientists at Emory University School of Medicine have been building a case for an answer. It's because motor neurons have long axons. And RNA must be transported to the end of the axons for motor neurons to survive and keep us moving, eating and breathing. Now the Emory researchers have a detailed picture for what they think the SMN protein is doing, and how its deficiency causes problems in SMA patients' cells. The findings are published in Cell Reports. "Our model explains the specificity -- why motor neurons are so vulnerable to reductions in SMN," says Wilfried Rossoll, PhD, assistant professor of cell biology at Emory University School of Medicine. "What's new is that we have a mechanism." Rossoll and his colleagues showed that the SMN protein is acting like a "matchmaker" for messenger RNA that needs partners to transport it into the cell axon. RNA carries messages from DNA, huddled in the nucleus, to the rest of the cell so that proteins can be produced locally. But RNA can't do that on its own, Rossoll says. In the paper, the scientists call SMN a "molecular chaperone." That means SMN helps RNA hook up with processing and transport proteins, but doesn't stay attached once the connections are made. "It loads the truck, but it's not on the truck," Rossoll says. Using fluorescence inside living cells as well as biochemistry, they showed that SMN promotes an interaction between the 'zipcode' region of a test RNA and a transport protein. Some of the experiments included cells from SMA patients, obtained through a collaboration with Han Phan, MD, a pediatric neurologist at Children's Healthcare of Atlanta, and the Laboratory for Translational Cell Biology at Emory. The first author of the paper is Paul Donlin-Asp, PhD, a former Biochemistry, Cell and Developmental Biology graduate student, now at the Max Planck Institute in Frankfurt,. Co-senior author is Gary Bassell, PhD, chair of the Department of Cell biology at Emory University School of Medicine. Scientists have known for 20 years that SMN is necessary in every cell of the body, since disrupting the gene in a mouse causes early embryonic death, before muscle or nerve cells form. However, humans have two SMN genes, one more than mice, so a mutation in the first gene usually leads to reduced levels of SMN protein but not its elimination. An antisense-based treatment called nusinersen, which removes a roadblock in the expression of the second SMN gene, was recently approved by the FDA. Rossoll says his team's research helps to clarify SMN's role in motor neurons and other cells, and insights into its function could be important for optimizing delivery of the newly available treatment or development of additional treatments. The research was supported by the Muscular Dystrophy Association, the Weissman Family Foundation, the National Institute of Neurological Disorders and Stroke (R01NS091749, F31NS084730, P30NS055077) and the ARCS Fellowship Roche Foundation.


News Article | November 9, 2016
Site: www.sciencedaily.com

Researchers at the University of Michigan have transplanted lab-grown mini lungs into immunosuppressed mice where the structures were able to survive, grow and mature. "In many ways, the transplanted mini lungs were indistinguishable from human adult tissue," says senior study author Jason Spence, Ph.D., associate professor in the Department of Internal Medicine and the Department of Cell and Developmental Biology at the U-M Medical School. The findings were published in eLife and described by authors as a potential new tool to study lung disease. Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain poor despite numerous therapeutic advances during the past 30 years. The numbers highlight the need for new, physiologically relevant models for translational lung research. Lab-grown lungs can help because they provide a human model to screen drugs, understand gene function, generate transplantable tissue and study complex human diseases, such as asthma. Lead study author Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology, used numerous signaling pathways involved with cell growth and organ formation to coax stem cells -- the body's master cells -- to make the miniature lungs. The researchers' previous study showed mini lungs grown in a dish consisted of structures that exemplified both the airways that move air in and out of the body, known as bronchi, and the small lung sacs called alveoli, which are critical to gas exchange during breathing. But to overcome the immature and disorganized structure, the researchers attempted to transplant the miniature lungs into mice, an approach that has been widely adopted in the stem cell field. Several initial strategies to transplant the mini lungs into mice were unsuccessful. Working with Lonnie Shea, Ph.D., professor of biomedical engineering at the University of Michigan, the team used a biodegradable scaffold, which had been developed for transplanting tissue into animals, to achieve successful transplantation of the mini lungs into mice. The scaffold provided a stiff structure to help the airway reach maturity. "In just eight weeks, the resulting transplanted tissue had impressive tube-shaped airway structures similar to the adult lung airways," says Dye. Researchers characterized the transplanted mini lungs as well-developed tissue that possessed a highly organized epithelial layer lining the lungs. One drawback was that the alveolar cell types did not grow in the transplants. Still, several specialized lung cell types were present, including mucus-producing cells, multiciliated cells and stem cells found in the adult lung.

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