Ludwig Cancer Research

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Ludwig Cancer Research

Brussels, Belgium

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News Article | May 12, 2017
Site: www.eurekalert.org

The loss of the tumor suppressor gene PTEN has been linked to tumor growth and chemotherapy resistance in the almost invariably lethal brain cancer glioblastoma multiforme (GBM). Now, Ludwig researchers have shown that one way to override the growth-promoting effects of PTEN deletion is, surprisingly, to inhibit a separate tumor suppressor gene. "It was an unexpected result because these are two verified tumor suppressor genes," said study senior author Frank Furnari, a member of Ludwig Institute for Cancer Research, San Diego. The finding, published in the current issue of the journal Nature Communications, could lead to new therapies for treating a common sub-type of GBM and possibly other forms of cancer. "PTEN is one of the most frequently deleted tumor suppressor genes in cancer, so if we can take our finding to the next level and develop a therapeutic around it, it could have wide utility," said Furnari, who is also a Professor of Pathology at the University of California, San Diego. In their study, Furnari and his colleagues detail a previously unknown physical interaction between PTEN and DAXX. The latter is a so-called chaperone protein that helps guide the attachment of the protein H3.3 to compact looping fibers of DNA and its protein scaffolding, which are collectively called chromatin. H3.3 is a variant of the histone protein H3. Most histone proteins are involved in helping package DNA into structures small enough to fit in the cell nucleus, but H3.3 appears to play a gene regulatory role instead. H3.3 has been found attached to chromatin sections containing tumor growth-promoting genes, or oncogenes, suggesting it helps suppress their activity. Thus, the discovery that PTEN interacts with DAXX indicates it can regulate oncogene expression in cells by affecting H3.3-chromatin binding. The work by the Ludwig scientists supports this hypothesis. "What we found was that PTEN suppresses oncogene expression by increasing the deposition of DAXX and H3.3 onto chromatin," Furnari said. In experiments involving mice injected with human GBM cells, the scientists also demonstrated that if either PTEN or DAXX were eliminated, then tumor growth occurred. However, if both genes are deleted, tumor growth slows--a phenomenon referred to as a synthetic growth defect. "We are proposing that in the absence of PTEN, DAXX competes with chromatin for H3.3, enabling the expression of oncogenes that would otherwise be suppressed," said study first author Jorge Benitez, a senior postdoc in Furnari's lab. "But if both PTEN and DAXX are deleted, then H3.3 is once again free to bind to the chromatin, slowing tumor growth." In their animal experiments, the team used genetic engineering techniques to knock out the DAXX gene, but they want to develop a drug that can achieve the same result. To that end, they are working to identify how exactly DAXX and H3.3 bind to one another. "The next step is to design molecules that can break that complex apart by binding to DAXX," Benitez said. "We think that is the first step on the way toward a therapeutic." Funding and support for this research was provided by Ludwig Cancer Research, the American Brain Tumor Society, the National Brain Tumor Society, and the James S. McDonnell Foundation. Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www. . For further information please contact Rachel Steinhardt, rsteinhardt@licr.org or +1-212-450-1582.


Preclinical data presented at AACR in April indicated an additive pharmacodynamic effect in primate models when Agenus' antibodies targeting CTLA-4 and PD-1 were co-administered. This, along with our clinical data, sets the stage for the Company's plans to combine these two molecules in a Phase 1b study in the second half of this year. The Company is also developing a next generation antibody targeting CTLA-4 as part of its innovative discovery pipeline.  This novel candidate exploits a distinct mechanism of CTLA-4 antagonism. It exhibits single agent potential and also combines effectively with Agenus' PD-1 antagonist, AGEN2034. Poster title: Phase 1 open-label, multiple ascending dose trial of AGEN1884, an anti-CTLA-4 monoclonal antibody, in advanced solid malignancies. Abstract number: #3075 Session title: Developmental Therapeutics - Immunotherapy Session date and time: Monday June 5, 2017; 8:00 am – 11:30 am The poster will become available on the Company's website at http://www.agenusbio.com/technology/publications/ following the poster session. AGEN1884 was developed under a Collaborative Research and Development Agreement between Ludwig Cancer Research, 4-Antibody AG and Recepta Biopharma S.A. AGEN1884 is partnered with Recepta Biopharma S.A. for certain South American rights. About Agenus Agenus is a clinical-stage immuno-oncology company focused on the discovery and development of therapies that engage the body's immune system to fight cancer. The Company's vision is to expand the patient populations benefiting from cancer immunotherapy by pursuing a number of combination approaches that leverage a broad repertoire of antibody therapeutics and proprietary cancer vaccine platforms. The Company is equipped with a suite of antibody discovery platforms and a state-of-the-art GMP manufacturing facility with the capacity to support early phase clinical programs. Agenus is based in Lexington, MA. For more information, please visit www.agenusbio.com; information that may be important to investors will be routinely posted on our website. Forward Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding the Company's upcoming poster presentation, plans to disclose safety and efficacy results and clinical trial plans and activities. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/agenus-to-present-safety-results-for-anti-ctla-4-antibody-at-asco-2017-annual-meeting-300461257.html


News Article | May 31, 2017
Site: www.eurekalert.org

Ludwig Cancer Research released today the full scope of Ludwig's participation at this year's American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, June 2-6. Ludwig scientists will present findings on efforts to diagnose and treat a variety of cancers, including melanoma, glioblastoma, multiple myeloma and lymphoma. "The ASCO Annual Meeting provides a unique opportunity for scientists from around the world to share information about new and innovative treatment strategies and identify new research opportunities," said Bob Strausberg, deputy scientific director, Ludwig Institute for Cancer Research. "Ludwig is pleased to present data on many advances, in cancer immunotherapy in particular, a field that has long been a focus of Ludwig research." Ludwig scientists will present four clinical trials of checkpoint antibody combination immunotherapies, which are jointly managed by Ludwig's Clinical Trials Management team and the Cancer Research Institute's Anna-Maria Kellen Clinical Accelerator. These include the evaluation of anti-CTLA-4 and anti-PD-L1 antibodies (i) to treat patients with advanced solid tumors, (ii) in combination with high dose chemotherapy and autologous stem cell transplant in multiple myeloma patients, and (iii) in-situ checkpoint immunotherapy in select accessible cancers. As part of this partnership, scientists will also share an update of a Phase II study to evaluate the safety and efficacy of an anti-PD-L1 therapy in newly diagnosed and relapsed glioblastoma patients. Further, a fifth study evaluating anti-CTLA-4 and anti-PD1 antibodies in combination with two different dose/fraction radiotherapy schemes will be presented. Ludwig researchers will also share findings on other topics, including the potential use of circulating tumor DNA in early diagnosis and treatment, immunotherapy to treat pediatric patients, how changes to DNA repair genes influence checkpoint blockade therapy, identifying biomarkers for melanoma treatment and diagnostic criteria for a type of lymphoma. Click here for a comprehensive list of Ludwig scientists' activities at the Meeting. Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www. . For further information please contact Rachel Steinhardt, rsteinhardt@licr.org or +1-212-450-1582.


News Article | July 17, 2017
Site: www.eurekalert.org

JULY 17, 2017, New York -- A Ludwig Cancer Research study offers pathologists a quick, cheap and reliable tool to diagnose diseases such as early breast cancer with a conventional optical microscope. In a paper published in the current issue of the journal Nature Biotechnology, an interdisciplinary research team led jointly by investigators at the Ludwig Center at Harvard and their colleagues at the Massachusetts Institute of Technology (MIT) demonstrates the utility of the new technique for microscopic diagnosis. Cellular features used to diagnose certain diseases can be a little too small to be studied reliably. Rather than focusing on increasing the power of microscopes themselves to improve observation of such structures, the researchers--led by Ludwig Harvard's Octavian Bucur and Andrew Beck, who recently left Ludwig Harvard to join PathAI as CEO, and Edward Boyden and Yongxin Zhao of MIT--tweaked the samples themselves. They clinically optimized a technique called expansion microscopy, developed by Boyden and his team at MIT, to expand the physical size of their specimens. This meant that the biopsies could be reliably studied with the kind of microscopes that are found in every pathology laboratory. "The most exciting thing is that we can use physical tissue expansion to push conventional optical microscopes beyond their limits, with important applications in diagnostic pathology and research," says Bucur, an investigator at the Ludwig Center at Harvard and the Department of Pathology and Cancer Research Institute at the Beth Israel Deaconess Medical Center, who is one of the two lead authors of the paper. "We can apply this method to any type of clinical sample and all types of human tissues, including normal and cancerous tissues," says Zhao, the other lead author of the paper. The optical microscope is an essential tool of the diagnostic pathology laboratory. But certain disease structures, including features of the filtration systems of the kidneys and early cancerous lesions of the breast are too small to be accurately studied. There are solutions to this problem, including electron microscopy. But such instruments are expensive and must be operated by specialized personnel. Boyden, an MIT professor of biological engineering and the co-director of the MIT Center for Neurobiological Engineering, pursued a different solution. His team figured out how to infuse biological specimens with swellable polymers--similar to the chemicals in baby diapers--in an even fashion, so that when water was added to the specimens, the cells or tissues would expand a hundredfold in volume. Boyden and colleagues demonstrated the uniform expansion of cells and mouse brain tissues in a 2015 Science paper. The method exploits a polymer network that swells uniformly within a tissue sample. After enzymatically cleaving the proteins in the tissue to prevent cracking, water is added to the sample, which has been treated with the polymer, to physically enlarge its finest structures. The technique, which the researchers call expansion microscopy, significantly improves the resolution of conventional microscopes. "In this way, we can image large-scale biological structures--like cancers, or brain circuits--with nanoscale precision, on ordinary microscopes," says Boyden. "My hope is that with expansion microscopy, we can begin to map the building blocks of life systematically, in health and disease states." The group at MIT teamed with Beck, Bucur and colleagues to optimize the method for diagnostic pathology and research. The team developed a pathology-optimized expansion microscopy to significantly improve the accuracy of computational discrimination between early pre-cancerous lesions with a high or a low risk for cancer transformation, testing their method on breast lesions of this type. This is notoriously difficult for pathologists to do. "Recent studies show that pathologists differ significantly in their diagnosis of early proliferative lesions," says Humayun Irshad, a postdoctoral fellow at the Ludwig Center at Harvard who developed the computational pipeline for this study. This has a significant impact on the treatment choice, potentially leading to overtreatment, such as unnecessary surgeries, or the neglect of cancers that require early intervention. "We think that an improved system for differentiating early lesions will potentially prevent hundreds of thousands of misdiagnoses every year in the US," says Beck. The team also showed that diagnosing certain kidney diseases, which currently requires electron microscopy, can now be performed with over 90% accuracy using expanded clinical samples and a conventional optical microscope. "Being able to eliminate the need for an electron microscope in diagnosing certain diseases will save a lot of money and enable a faster and easier diagnosis for those particular diseases," says Bucur. The team is currently working to make pathologists aware of the new technique and testing other applications for the method, including studying drug resistance in breast cancer. This research was funded by The Ludwig Center at Harvard, Harvard Catalyst, the Open Philanthropy project, the HHMI-Simons Faculty Scholars Program, the U.S. Army Research Laboratory and the U.S. Army Research Office, NIH, and the New York Stem Cell Foundation-Robertson Investigator Award. Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www. . For futher information please contact Rachel Steinhardt, rsteinhardt@licr.org or +1-212-450-1582.


News Article | September 20, 2016
Site: www.rdmag.com

A Ludwig Cancer Research study published online September 14th in Nature reports a novel technique to map specific chemical (or "epigenetic") modifications made to the protein packaging of DNA using a small population of cells. Such epigenetic marks play a central role in the regulation of the genome's expression. Led jointly by Ludwig San Diego's Bing Ren and Arne Klungland of the University of Oslo, the authors describe their application of this method to unravel a key mystery of the earliest stage of development. The new technique, named μChIP-seq, is also likely to be of notable relevance to cancer research. Very soon after fertilization, the control of embryonic development shifts from pre-existing maternal gene products to the products of genes encoded by the early embryo (or zygote). This passing of the genetic baton, called the maternal-to-zygotic transition (MZT), is poorly understood because existing technologies have generally been too insensitive to capture the full scale of the epigenetic changes it entails across the zygotic genome. The improved sensitivity of μChIP-seq, developed jointly by Klugland, Ren and John Arne Dahl of Oslo University, led to "some remarkable discoveries that have completely changed our view of epigenetic inheritance mechanisms," says Ren. In the current paper, Ren and his colleagues describe their use of μChIP-seq to investigate how epigenetic information is passed from one generation to the next to orchestrate the MZT. To that end, they examined in mouse embryos the global distribution of an epigenetic mark known to play a critical role in regulating the activity of genes. This mark (H3K4me3) modifies chromatin—the complex of DNA and its protein packaging—by adding three identical molecules known as methyl groups at a specific place on a packaging protein known as histone 3. Dahl, a visiting scholar in Ren's lab and co-first author on the Nature paper, fine-tuned the technique for mapping such epigenetic tags to where only a few hundred embryos or cells were needed for each experiment. Previous methods required up to 10,000 cells to conduct similar analyses. The other first author, Inkyung Jung, a Ludwig postdoc in Ren's lab, contributed significantly to the computational analysis of the resulting data. When the scientists compared H3K4me3 distribution in immature mouse egg cells they found something unexpected: broad but distinct domains of the immature egg cell's genome, representing some 22% of the whole, are heavily marked by H3K4me3. These domains rapidly decrease in size in 2-cell embryos and eventually shrink to about 1% to 2% of the genome. "The key lesson we learned was that the genes that are destined to be turned on specifically in the fertilized egg are covered by this unique chromatin domain structure," says Ren. Those marks have to be removed by specialized enzymes to activate the zygotic genome. "This mark is a mechanism for the oocyte to influence which genes in the zygote are activated. It is an epigenetic mechanism for the passage of information from the maternal oocyte to the zygote." The ability to map "epigenomes" using such a small number of cells will be valuable to cancer research, since the epigenetic landscape is dramatically rearranged in cancer and contributes to phenomena driven by small subpopulations of cells, such as drug resistance and metastasis. "With a better understanding of the epigenetic landscapes in cancers, we are going to have more tools to study the basis of tumorigenesis," says Ren. "We still have a long way to go, but our goal is to have a thorough understanding of gene regulatory programs so we can use that knowledge to treat cancer and develop diagnostic tools."


News Article | March 2, 2017
Site: www.eurekalert.org

Ludwig researchers have shown that triple-negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy and that targeting this pathway could undermine their resistance to such therapies. MARCH 2, 2017, New York -- A team of researchers led by Alex Toker of the Ludwig Center at Harvard has discovered a metabolic weakness in triple-negative breast cancer (TNBC) cells that may be exploited to quell their resistance to chemotherapy. TNBC is notoriously aggressive and is difficult to treat because its cells lack the targetable receptors found in other forms of breast cancer. Only about 30 percent of TNBC patients achieve a pathologic complete response, or a complete eradication of active cancer cells, following chemotherapy. Those who do frequently relapse shortly afterward. "Trying to understand the mechanisms that contribute to cancer's resistance to therapy is a major mission here at the Ludwig Center at Harvard," said Alex Toker. In the new study, published online in the journal Cancer Discovery, Toker, an investigator at the Ludwig Center at Harvard Medical School, and his team including lead author Kristin Brown, formerly of the Ludwig Center at Harvard and now at Peter MacCallum Cancer Center in Melbourne, Australia, outline a newly discovered chink in the armor of TNBC cells. This "metabolic vulnerability" can be used to circumvent chemotherapy resistance. The scientists demonstrated that chemotherapy effectively reprograms TNBC cells to ramp up production of the pyrimidine nucloetides, key building blocks of DNA. This heightens the cells' DNA repair abilities and ultimately results in greater resistance to chemotherapies that work by damaging the DNA of rapidly dividing cells. "This actually makes sense if you think about it, because if a tumor cell is going to repair DNA and therefore evade the death-inducing effects of chemotherapy, the only way they can really do that is by rebuilding DNA, and the only way to rebuild DNA is to make more nucleotides," Toker said. Toker and his team reasoned that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities and make them more susceptible to the DNA-damaging effects of chemotherapy. To test this hypothesis, the team exposed TNBC cells in the lab to a drug combination of doxorubicin, a commonly used chemotherapy agent, and leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a crucial enzyme in the biochemical reactions that generate pyrimidines. "One of the major reasons we chose leflunomide is because we wanted a rapid path to clinical impact, and leflunomide is already FDA-approved and widely used to treat autoimmune diseases such as rheumatoid arthritis," Toker said. Toker's group found that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, thus impairing their ability to repair the DNA damage dealt by doxorubicin, and resulting in increased cancer cell death. The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. "We found that treating the mice with doxorubicin or leflunomide alone only slowed tumor growth, but that a combination therapy involving both drugs resulted in significant tumor regression," Toker said. Importantly, the combination therapy in mice did not cause any weight loss or gain in the animals - an indication that the drug regimen might be reasonably well-tolerated in humans. "One of the things we would like to do is develop clinical trials in patients with this combination strategy, whether it be with leflunomide or some other drugs that are coming online that might have better pharmacological properties in patients," Toker said. In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells. "There is something about this pathway in triple negative breast cancer that is especially important," Toker said. "We don't know what the genetic basis underlying it is, but it's something we would really like to find out." Funding and support for this research was provided by the Virginia and DK Ludwig Fund for Cancer Research. Alex Toker, an investigator at the Ludwig Center at Harvard, is also a professor in the Department of Pathology at the Beth Israel Deaconess Medical Center and Harvard Medical School and Chief of the Division of Signal Transduction in the Departments of Medicine, Pathology and Cancer Center. Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www. . For further information please contact Rachel Steinhardt, rsteinhardt@licr.org or +1-212-450-1582.


News Article | April 8, 2016
Site: www.rdmag.com

Researchers at Karolinska Institutet and the Ludwig Cancer Research in Stockholm, Sweden have conducted a detailed molecular analysis of the embryo's first week of development. Their results show that there are considerable differences in embryonic development between humans and mice, which is the most common organism of study in this field. The new study, which is published in the journal Cell, also shows that genes on the X chromosome are regulated differently. Early human embryonic development is difficult to study, and most of our knowledge comes from mice. During the first seven days of fertilization, the egg develops from a single cell to a blastocyst, a hollow cluster of some 200 to 300 cells. It is during this time that the first three cell types appear: the trophectoderm, which gives rise to the placenta, the hypoblast, which forms the embryonic endoderm, and the embryonic cells that go to make up the embryo itself. If the embryo is to adhere to the uterus wall and pregnancy commences, all these three cell types must mature properly. However, exactly when and in which order and how the cell types form in humans has not been known. By detecting gene expression in individual cells, from donated human embryos that were not used for IVF treatment, two research groups led by Rickard Sandberg and Fredrik Lanner have managed to identify which genes are used in the embryo's cells at different times during the first week of development. They found that the first three cell types form later and seem to mature more simultaneously in the human than in the mouse. "The fundamental knowledge generated by our research doesn't only help us understand embryonic development better, it also tells us more about how pluripotent cells are formed and regulated in its early stages," said Lanner at Karolinska Institutet's Department of Clinical Science, Intervention and Technology. "This is important for the use of embryonic stem cells in regenerative medicine." The researchers also found that the expression of genes situated on the X chromosome is subject to an unexpected expression pattern. The X chromosome has a particular gene regulation problem, since women's cells have two X chromosomes, while men only have a copy (XY). To avoid women having twice the level of expression of all genes on the X chromosome as men, women's cells must offset the gene expression. In mice, where this process is well-studied, one of the two X chromosomes is simply shut off during the first week. However, it has always been uncertain if this process even begins during the first week of human embryo development. "What we've been able to demonstrate is that dose balance is gradually attained during day 4 to 7, interestingly through a completely new manner in which the gene expression from both X chromosomes in the female embryo is suppressed," said Sandberg.


News Article | November 1, 2016
Site: phys.org

When information in our genes is used, for example to build a protein, it is first translated to messenger-RNA which functions as a blueprint for the protein. Our cells also contain non-coding, short, RNA sequences that do not contribute to the formation of proteins and whose functions are partly unknown. The best known of these is micro RNA (miRNAs), which can interact with the messenger RNA, and thereby regulate genes and cell function. Researchers at Karolinska Institutet have now mapped the presence of short RNA-sequences in an individual cell. Previous research on short RNA molecules is based on analysis of many cells simultaneously, making it difficult to study the precise function. "Our knowledge of the function of short RNA molecules is quite general. We have a picture of the general mechanisms, but it is less clear what specific role these molecules play in different types of cells or diseases," says Rickard Sandberg, professor at the Department of Cell and Molecular Biology, who is also affiliated to the Stockholm center of Ludwig Cancer Research. The analysis was done using single-cell transcriptomics, a technique which makes it possible to measure the absolute numbers of short RNA molecules in a cell. Two types of embryonic stem cells were used, intended to mimic the early embryo, before and after it has attached to the uterine lining. The researchers could detect large numbers of small RNAs in both cell states, including miRNA as well as shorter RNA fragments (tRNA and snoRNA) whose function is largely unknown. The researchers also found that large numbers of miRNAs are expressed differently in the two cell states. "This is basic research and a demonstration that the method works, giving suggestions for further research. To map the levels of short RNA molecules in a cell is a first step in identifying the specific function of these molecules," says Omid Faridani, one of the lead authors of the study. In the long run, Rickard Sandberg can imagine clinical applications of the method. "We are, for example, interested in the role short RNA molecules play during embryonic development. We hope that, with more knowledge, this method could be used to identify which embryos have the best chance to develop, which would then be used to improve current IVF treatments," he says. Explore further: New insights into early human embryo development More information: Omid R Faridani et al, Single-cell sequencing of the small-RNA transcriptome, Nature Biotechnology (2016). DOI: 10.1038/nbt.3701


News Article | November 1, 2016
Site: www.eurekalert.org

Researchers at Karolinska Institutet have measured the absolute numbers of short, non-coding, RNA sequences in individual embryonic stem cells. The new method could improve the understanding of how our genes are regulated and different cell types develop. When information in our genes is used, for example to build a protein, it is first translated to messenger-RNA which functions as a blueprint for the protein. Our cells also contain non-coding, short, RNA sequences that do not contribute to the formation of proteins and whose functions are partly unknown. The best known of these is micro RNA (miRNAs), which can interact with the messenger RNA, and thereby regulate genes and cell function. Researchers at Karolinska Institutet have now mapped the presence of short RNA-sequences in an individual cell. Previous research on short RNA molecules is based on analysis of many cells simultaneously, making it difficult to study the precise function. "Our knowledge of the function of short RNA molecules is quite general. We have a picture of the general mechanisms, but it is less clear what specific role these molecules play in different types of cells or diseases," says Rickard Sandberg, professor at the Department of Cell and Molecular Biology, who is also affiliated to the Stockholm center of Ludwig Cancer Research. The analysis was done using single-cell transcriptomics, a technique which makes it possible to measure the absolute numbers of short RNA molecules in a cell. Two types of embryonic stem cells were used, intended to mimic the early embryo, before and after it has attached to the uterine lining. The researchers could detect large numbers of small RNAs in both cell states, including miRNA as well as shorter RNA fragments (tRNA and snoRNA) whose function is largely unknown. The researchers also found that large numbers of miRNAs are expressed differently in the two cell states. "This is basic research and a demonstration that the method works, giving suggestions for further research. To map the levels of short RNA molecules in a cell is a first step in identifying the specific function of these molecules," says Omid Faridani, one of the lead authors of the study. In the long run, Rickard Sandberg can imagine clinical applications of the method. "We are, for example, interested in the role short RNA molecules play during embryonic development. We hope that, with more knowledge, this method could be used to identify which embryos have the best chance to develop, which would then be used to improve current IVF treatments," he says. "Single-cell sequencing of the small-RNA transcriptome" Omid R. Faridani, Ilgar Abdullayev, Michael Hagemann-Jensen, John P. Schell, Fredrik Lanner and Rickard Sandberg Nature Biotechnology, online 31 October 2016. DOI: 10.1038/nbt.3701


News Article | October 26, 2016
Site: www.eurekalert.org

Tumor cells collected during the removal of a cancerous bladder and - in some cases - transplanted into mice with weakened immune systems, could help physicians rapidly identify high-risk cancers, determine prognosis and refine the use of biomarkers to personalize care for patients with this common cancer, according to a study published online on Oct. 24, 2016, in Scientific Reports (one of the Nature journals). The researchers, based at the Ludwig Center at the University of Chicago, found that detection of poorly differentiated basal tumor cells in early stage cancers; overexpression in those cells of a gene known as cell division cycle 25C, which plays a key role in the regulation of cell division; or the ability of tumor fragments to grow when transplanted into a mouse, all predicted an increased risk of death. "If confirmed in larger studies, our findings could help physicians get a better handle on how a patient's bladder cancer is likely to progress and allow them to personalize treatment based on that knowledge," said study author Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology and Chair of the Department of Radiation and Cellular Oncology at the University. Bladder cancer is the fourth most common cause of cancer-related death among men in the United States. More than 75,000 new cases will be diagnosed this year and more than 16,000 people will die from this disease. Weichselbaum and colleagues obtained tumor samples from 71 bladder cancer patients treated at the University and used flow cytometry to isolate and count specific subtypes of tumor cells in each sample. They showed that an excess of one relatively rare subtype in early-stage cancers - the basal tumor cell (BTC) - was associated with a 3-fold increase in risk of death. Analyzing the global expression of genes in BTCs, the researchers also identified a potentially prognostic biomarker for bladder cancer: cell division cycle 25C (CDC25C), a protein that drives cell division. An expanded analysis, including 400 bladder cancer patients, found that the expression of this protein is associated with an increased risk of death even after the removal of the cancerous bladder. This association disappeared in patients who had previously received chemotherapy. A test for CDC25C could, the authors suggest, help determine whether a bladder cancer patient is likely to benefit from drug treatment. In more invasive tumors, the presence and number of BTCs had less prognostic value. When the researchers injected bladder-cancer tissue fragments from 69 patients with more advanced cancers into the flanks of immune-deficient mice, however, about 60 percent of these tumor fragments were able to take hold and grow in this setting. This was associated with a 6-fold increase in risk of death, compared to tumor fragments that did not survive and grow after transplantation. "Prognostic knowledge can change a lot about how you choose to treat a cancer," said Weichselbaum. "We may be able to avoid aggressive measures if we find a tumor has relatively few basal cells," he said. "We could treat an early-stage bladder cancer with less aggressive therapy, avoiding debilitating interventions like radical cystectomy. But if a bladder tumor has a lot of basal cells, we may need to take the entire bladder out and follow that with chemotherapy. Before this can happen, he added, the accuracy of his team's new prognostic model and biomarker "will need to be confirmed in larger studies." The study was supported by Ludwig Cancer Research, Rosalind and Burton Spellman Family Cancer Fund, The Foglia Foundation and Mr. and Ms. Vincent Foglia. Additional authors were K. B. Skowron, S. P. Pitroda, J. P. Namm, O. Balogun, M. A. Beckett, M. L. Zenner, O. Fayanju, X. Huang, C. Fernandez, W. Zheng, G. Qiao, R. Chin, S. J. Kron, N. N. Khodarev, M. C. Posner and G. D. Steinberg.

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