Day 1 :
Keynote Forum
Mukesh Verma
National Institutes of Health, USA
Keynote: Challenges and research opportunities in metabolomics
Time : 10:05-10:30
Biography:
Mukesh Verma is a Program Director and Chief in the Methods and Technologies Branch (MTB), Epidemiology and Genetics Research Program (EGRP) of the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute (NCI), National Institutes of Health (NIH). Before coming to the DCCPS, he was a Program Director in the Division of Cancer. Prevention (DCP), NCI, providing direction in the areas of biomarkers, early detection, risk assessment and prevention of cancer, and cancers associated with infectious agents. He holds an MSc from Pantnagar University and a PhD from Banaras Hindu University. He did Postdoctoral research at George Washington University and was a faculty member at Georgetown University. He has published 136 research articles and reviews and edited three books in cancer epigenetics and epidemiology field.
Abstract:
Epidemiology, the study of frequency, distribution, and determinants of disease in human population has gained awareness of its contribution in the advancement of biomedical knowledge over the past several decades. Epidemiologic studies not only offer the opportunities to generate hypotheses through the descriptive nature of the study design, but also provide chances to extrapolate the knowledge gained from laboratory experiments to human and generalize the finding from clinical trials to the general population. Through the course of epidemiologic study design, the hypotheses can be verified for primary prevention strategies and the secondary and tertiary prevention efforts can be evaluated for its effectiveness and efficiency.Although success has been achieved in metabolomic studies, few challenges and research opportunities have come across. One of the challenges of applying metabolomics in epidemiologic studies is to differentiate environmental influences on the metabolome from normal aging of the metabolome which in itself can be associated with age-related illness, such as cancer, diabetes mellitus, and cardiovascular diseases. Additionally, environmental exposures play an important role in shaping the metabolomic signatures, hence can have a significant contribution to epidemiologic studies in understanding its role in disease causation. Population-based studies are an excellent tool to better understand the relationship between metabolomic variations and disease distribution.Epidemiologist employs a number of different study designs (cross-sectional studies, retrospective case-control studies, cohort studies, nested case control studies, intervention studies, family-based studies, birth cohorts) that can be used to study the role of metabolomics in health and diseases.
Keynote Forum
Jian Zhi Hu
Pacific Northwest National Laboratory, USA
Keynote: High Resolution NMR Metabolomics on Biological Tissues and Live Objects
Time : 10:30-10:55
Biography:
Jian Zhi Hu has completed his PhD at the age of 32 years from a Joint-Training Program between Wuhan Institute of Physics, the Chinese Academy of Sciences and the Department of Chemistry, University of Utah, USA, and postdoctoral studies from University of Utah.He is a senior staff scientist and principal investigator of Pacific Norwest National Laboratory.He has published more than 160 papers in reputed journals. He received one US R&D 100 award and is a holder of 8 issued US patents.
Abstract:
Metabolomics studies on biological tissues are of significance since a disease is often associated with a specific tissue or organ malfunction. In this talk, high resolution NMR metabolic profiling techniques on biological tissues and live objects will be discussed. I’ll start with traditional liquid state 1H NMR metabolic profiling on tissue extracts using metastatic melanoma in C57BL/6J mouse spleen as an example to illustrate the procedures and methods associated with tissue extraction, metabolic profiling, data analysis, biostatics and bioinformatics. With this example, we are able to identify 73 metabolites with estimated concentrations in spleen tissue ranged from as low as 6 uM to as high as 25mM in the hydrophilic extracts of a spleen. The second part of the talk will cover the topic of high resolution magic angle spinning (MAS) NMR metabolomics on intact biological tissues. Fast MAS using a sample spinning rate of several kHz or more that is destructive to the integrity of a biological tissue will be discussed first, followed by slow-MAS NMR metabolomics using a sample spinning rate of 40 to about 200 Hz that is essentially non-destructive to biological tissues and even small intact live biological objects such as live insects and bugs. Finally, ultra-slow MAS NMR metabolomics using a sample spinning rate of 1-6 Hz will be introduced that is non-destructive to a live laboratory animal such as a mouse.
Networking & Refreshments Break 10:55-11:10 @ Independence Foyer
- Metabolomics and Cancer Research
Track 2: Analytical Techniques in Metabolomics
Track 3: Applications of Separation Sciences in Metabolomics
Track 4: Frontiers of Metabolomics Research
Chair
Mukesh Verma
NIH, USA
Co-Chair
Paola Marignani
Dalhousie University, Canada
Session Introduction
Stefan Kempa
BIMSB, Germany
Title: Using stable isotope resolved metabolomics to characterize glycolytic inhibition and to decode synthetic lethality in cancer
Time : 11:10-11:30
Biography:
Stefan Kempa has completed his PhD at the University of Potsdam and performed his Postdoctoral studies at the IMBA/GMI in Vienna focusing on the crosstalk between signaling and metabolism in plants. He is leading a Research and Technology Group at the Berlin Institute for Medical Systems Biology-Max Delbruck Center in Berlin, Germany
Abstract:
Metabolic reprogramming is a key step in oncogenic transformation including the activation of energy and anabolic metabolism. The central metabolism is the ultimate source of energy and building blocks enabling growth and proliferation. Specifically, time-resolved analysis of central metabolic pathways is needed for a better understanding of metabolic dynamics and the comparison and even quantification of pathway usage. In order to quantify the usage and activity of central metabolic pathways we have developed pulsed stable isotope resolved metabolomics (pSIRM) to analyse metabolism in vitro and in vivo. The applied GC-MS based technology enables the absolute quantification of metabolites and at the same time the determination of stable isotope incorporation, thus it allows also quantifying metabolic dynamics in vivo. Since the observation that glycolysis is deregulated in cancer the central metabolism gained attention as a possible therapeutic target. We have characterized the action of glycolytic inhibitors using pSIRM in a time dependent manner to distinguish between actual metabolic inhibition and adaptive processes. We observed unexpected effects and argue that the commonly used compound 2-deoxyglucose is not a specific glycolytic inhibitor. In order to understand the metabolic vulnerabilities at a molecular level we together with our co-workers have investigated the metabolic aspect of synthetic lethal interaction around the oncogene cMyc and could uncover metabolic circuits in regulatory networks that may open new ways for combinatorial therapies including metabolic inhibition.
Mukesh Verma
NIH, USA
Title: Title: Metabolomic approaches in cancer epidemiology
Time : 11:30-11:50
Biography:
Mukesh Verma is a Program Director and Chief in the Methods and Technologies Branch (MTB), Epidemiology and Genetics Research Program (EGRP) of the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute (NCI), National Institutes of Health (NIH). Before coming to the DCCPS, he was a Program Director in the Division of Cancer Prevention (DCP), NCI, providing direction in the areas of biomarkers, early detection, risk assessment and prevention of cancer, and cancers associated with infectious agents. He holds an MSc from Pantnagar University and a PhD from Banaras Hindu University. He did Postdoctoral research at George Washington University and was a faculty member at Georgetown University. He has published 136 research articles and reviews and edited three books in cancer epigenetics and epidemiology field
Abstract:
Metabolomics is the study of low molecular weight molecules or metabolites produced within cells and biological systems. It involves technologies, such as mass spectrometry (MS) and nuclear magnetic resonance spectrography (NMR), which can measure hundreds to thousands of unique chemical entities (UCE). The metabolome provides one of the most accurate reflections of cellular activity at the functional level and hence can be leveraged for discerning mechanistic information during different normal and disease states. In clinical samples metabolites are more stable than proteins or RNA. In fact, metabolomic profiling in basic, epidemiological, clinical and translational studies has revealed potential new biomarkers of disease and therapeutic outcome and led to novel mechanistic understanding of pathogenesis. These include the recent biomarkers for diabetes risk, novel metabolites associated with cancer, and the discovery of over 500 unique lipids in plasma. However, unlike genomics or even proteomics, the degree ofmetabolite complexity and heterogeneity within biological systems presents unique challenges requiring specialized skills and resources to overcome. An example of association of metabolomics predictors of body fat amount and distribution and associated risk with cancer will be discussed. Epidemiology studies with altered metabolite profiles in lung, prostate, and endometrial cancer will also be discussed.
Jian Zhi Hu
Pacific Norwest National Laboratory, USA
Title: Non-, or minimally invasive intact biological objects using slow magic angle spinning
Time : 11:50-12:10
Biography:
Jian Zhi Hu has completed his PhD at the age of 32 years from a Joint-Training Program between Wuhan Institute of Physics, the Chinese Academy of Sciences and the Department of Chemistry, University of Utah, USA, and Postdoctoral studies from University of Utah. He is a Senior Staff Scientist and Principal Investigator of the Pacific Norwest National Laboratory. He has published more than 160 papers in reputed journals. He received one US R&D 100 award and is a holder of 8 issued US patents.
Abstract:
Metabolomics studies on tissues are of significance since a disease is often associated with a specific tissue or organ malfunction. It is, therefore, expected that the changes in metabolic profile are more dramatic in the diseased tissue than body fluids. It is likely that tissue specific metabolic profiling provides a unique window of investigating the biochemistry associated with a particular disease in greater detail than possible using global body fluids. In this work, we will report a non-destructive magic angle spinning NMR metabolomics technique that is capable of high resolution and high sensitivity metabolic profiling of biological samples, in particular tissue samples, with sample volume from as small as 200 nanoliters (nL) to as large as a milliliter or more using a single probe and using only a few minutes. This has been achieved by combining a the techniques of high resolution slow-MAS 1H NMR technique and switchable inductively coupled static micro-RF coil-LC resonator and by rotating the specimen at a sample spinning rate of 40 to 200 Hz about the magic angle axis. The nanoliter capability has the potential to follow the metabolic changes through a continued investigation on a single small laboratory animal over a long period of time using minimally invasive blood and tissue biopsy samples. While the milliliter capability would allow minimally destructive studies of intact biological objects with size as large as >1 cm3. Examples of applications will be reported.
Paola Marignani
Dalhousie University, Canada
Title: Targeting cancer metabolism to overcome treatment resistance in HER2-positive breast cancer.
Time : 12:10-12:30
Biography:
Dr. Paola Marignani received her PhD from McMaster University, followed by Postdoctoral fellowships at Harvard, the Samuel Lunenfeld Research Institute and the Ontario Cancer Institute. The Marignani Discovery Research Laboratory uses animal models and high through-put screening strategies to identify novel signalling pathways involved in disease. Dr. Marignani and her team have shown that the tumour suppressor kinase LKB1 is an interacting partner and regulator of the estrogen receptor. More recently her team developed a novel spontaneous mouse model of breast cancer. In this model, proteomic and metabolic profiling of tumours confirm hyperactive mTOR and metabolic activity. By combining multiple platforms, The Marignani Discovery Research Laboratory continues to focus on identifying molecular switches that drive tumourigenesis, conduct pre-clinical trials that evaluate novel targeted therapies and develop clinically relevance animals models of human disease.
Abstract:
Metabolic adaption of tumour cells is necessary to meet biosynthesis and energy needs of a growing cancer. The energy sensing kinase AMPK is responsible for maintaining AMP/ATP ratio, serving as a metabolic checkpoint that is activated when phosphorylated by the LKB1, a tumour suppressor kinase. LKB1 is frequently found mutated in numerous cancers including 31% of HER2 breast cancer. In our LKB1-/-NIC model, loss of LKB1 expression resulted in reduced tumour latency where tumours were biochemically characterized as hyperactive mTOR, along with metabolic changes characteristic of Warburg effect, namely elevated ATP, LDH, PDH expression and enhanced lactate. Based on these finding, we conducted a pre-clinical studies to evaluate novel combinatorial therapies on tumourigenesis. We report that targeting PI3K-p70S6K pathways with competitive NVP-BEZ235 inhibitor was not as effective at reducing tumourigenesis as targeting mTOR and glycolysis with AZD8055 and 2-DG monotherapies, respectively. Interestingly, simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing mitochondria function, tumour volume and burden, culminating in reduced tumourigenesis. At the molecular level, combination treatment inhibited both mTOR signalling and blocked MAPK survival signalling that is responsible for ERK-p90RSK pathway engagement. Finally, loss of LKB1 expression in cancers should be considered a marker for metabolic dysfunction given the role LKB1 plays in regulating both AMPK activity and mTOR function. The results of our pre-clinical studies suggest that combinatorial therapy that target mTORC1/mTORC2 and glycolytic pathways in cancer, is critical for inhibiting tumour growth. Importantly, our discovery showed that the drug combination inhibited the activation of feedback loops that are drivers of resistance, namely ERK and p90RSK. We believe that simultaneous targeting of these pathways will provide the best clinical outcome for the treatment of metabolically active cancers, as well as reduce the likelihood of recurrence.
Li Zhang
The University of Texas, USA
Title: Evaluating the association of heme and heme metabolites with lung cancer energetics and progression
Time : 12:30-12:50
Biography:
Li Zhangcompleted herPhD from UCLA and postdoctoral studies from MIT department of Biology.She is Cecil H. and Ida Green Distinguished Chair in Systems Biology Science at the University of Texas at Dallas. Professor Zhang has worked on studying heme signaling and function for 20 years. She has published many original research articles and a book entitled “Heme Biology: The Secret Life of Heme in Regulating Diverse Biological Processes” on this subject.
Abstract:
Emerging experimental data increasingly show that despite the enhanced glycolytic flux,many types of cancer cells exhibit intensified oxygen consumption or mitochondrial respiration. Even under hypoxia, cancer cells can maintain oxidative phosphorylation at a substantial rate. Heme is a central factor in oxygen utilization and oxidative phosphorylation. It serves as a prosthetic group in many proteins and enzymes involved in mitochondrial respiration. Notably, our recent work showed that non-small-cell lung cancer (NSCLC) cells and xenograft tumors exhibit substantially increased levels in an array of proteins promoting heme synthesis, uptake and function. These proteins include the rate-limiting heme biosynthetic enzyme ALAS, transporter proteins, and various types ofoxygen-utilizing hemoproteins such as cytoglobin and cytochromes. In contrast, lowering hemebiosynthesis and uptake, like lowering mitochondrial respiration, effectively reduced oxygenconsumption, cancer cell proliferation, migration and colony formation. Therefore, elevatedheme function and flux are likely a key feature of NSCLC cells and tumors. Based on this observation, we decided to further ascertain the relationship between heme and lung cancer. We extract heme and its metabolites from various NSCLC cancer cells and tumors. We then perform LC-mass spectrometry to quantify the amounts of heme and its metabolites. We also measure the rates of oxygen consumption in various cancer cells and compare them to the levels of heme in these cells. We expect that these experimental results will enable us to determine the extent to which heme and heme metabolites impact cancer cell bioenergetics and progression
Jayoung Kim
Cedars-Sinai Medical Center, USA
Title: Non-invasive biomarker candidates of Interstitial cystitis
Time : 12:50-13:10
Biography:
Jayoung Kim is an NIH-funded translational scientist and an Associate Professor at Cedars-Sinai Medical Center. She aims to improve the means of objectively diagnosing IC/PBS and to discover the mechanistic basis for this disorder. She was originally trained as a cancer biologist at Harvard Medical School, and is a rising leader of research on basic urological diseases including IC/PBS. One of the major focus areas in her group is the study of the metabolic signature for the diagnosis of IC/PBS, using a number of approaches, including large-scale “Omics” methods, to elucidate the signaling network in human cells that is perturbed in IC/PBS
Abstract:
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating condition that presents with a constellation of symptoms including bladder pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies. A lack of objective diagnostic criteria has affected our ability to adequately treat the disease. The goal of this proposed study is to identify/validate sensitive and non-invasive diagnostic biomarkers using urine specimens that stratify IC/PBS patients from healthy subjects. NMR spectroscopy-based metabolomics analysis was performed to search for soluble metabolites that segregate with the diagnosis of IC/PBS. Annotation of the NMR peaks was performed using MeltDB and MetaboloAnalyst software. It was able to annotate several of the discriminant peaks, including the most significant peak, which was identified as tyramine, a neuro-transmodulator related to pain. These results demonstrate our ability to assay for and provisionally identify discrete urine metabolites that are significantly associated with IC/PBS. This study is believed to provide novel insights about the etiology of IC/PBS and identify urine metabolites as biomarkers of IC/PBS that have the potential to be employed clinically.
Yongyu Zhang
Shanghai University of Traditional Chinese Medicine, China
Title: Metal Element on Non-alcoholic Fatty Liver Disease(NAFLD)
Time : 14:10-14:30
Biography:
Yongyu Zhang has completed his PhD from Meiji Pharmaceutical University in Japan, 2000. He is a Professor of Shanghai University of Traditional Chinese Medicine. He has published more than 20 papers in reputed journals and has been serving as an Editorial Board Member of 3 journals.
Abstract:
Our group has been devoted to researching the mechanism, development and treatment of the diseases under the guidance of Traditional Chinese Medicine (TCM) theory through metabolomics for many years. Results of the researches indicated that the “Tongbing Yizheng” theory, namely the same disease could be divided into different groups based on the TCM theory, has its substantial basis at the metabolic level. Meanwhile, we also found that some metal elements played a role in the classification of TCM syndrome. So we introduce the metabolomics basing on ICP-MS and HPLC-ICP-MS which is a new member of the omics family into our research on the substantial basis of dampness - heat Syndrome, one of common syndromes in TCM. Twenty-six elements were quantitatively detected in the serum samples of model rats with dampness - heat Syndrome, which was combined with sesum metabolomics to investigate the connotation of dampness-heat syndrome. Eleven differential metabolites and 4 changed elements including Zn, Fe, Se and Cu were found between normal group and dampness-heat syndrome group. After the pathway analysis it was found that the dampness-heat syndrome was related with cyanoamino acid metabolism, nitrogen metabolism, thiamine metabolism, butanoate metabolism, mineral absorption, two-component system and ABC transporters. The present results indicate that the combination of metabolomics and metabolomics could provide an approach to research the TCM subtypes of diseases.
Ih-Jen Su
National Health Research Institutes, Taiwan
Title: Dynamic pattern and terminal switch of lipid metabolomics in HBV tumorigenesis
Time : 14:30-14:50
Biography:
Dr. Su received his MD degree from National Taiwan University Medical School in 1976, and PhD degree in Pathology in 1987. His major research interest is virus and virus-associated human cancers. He was the pioneer investigator in EBV-associated T cell lymphoma, and was appointed as the member of International Lymphoma Study Group ( 1996-2008 ) for WHO lymphoma classification. During the SARS period, he served as the Director General of Taiwan CDC and successfully controlled SARS. In 2011-2013, he was appointed as the Director of National Institutes of Infectious Diseases and Vaccinology, NHRI to develop vaccines for EV71, H7N9, and BCG. In the past decade, he become interested in HBV carcinogenesis andidentified pre-S2 mutants as the new viral oncoproteins, and ground glass hepatocytes as pre-neoplastic lesions. He studied the cancer metabolomics and started to apply these biomarkers, especially mTOR and c-myc signals, for chemoprevention of high risk chronic HBV carriers. He published a total of around 300 papers, many of which in the prestigious journals like Lancet, Blood, Journal of Clinical Investigation, Hepatology, etc. His many studies have been translated into clinical application and industry development.
Abstract:
Background: The lipid metabolic disorders were frequently observed in patients of HBV and HCV-associated hepatocellular carcinoma (HCC). The underlying mechanism and significance remains to be clarified. Aim: In this study, we attempt to clarify the role of lipid metabolism in HBV tumorigenesis. Methods: The dynamic, temporal pattern of lipid metabolic profiles in serum and lipid were demonstrated in two transgenic mice models of HBx and pre-S2 deletion mutant by biochemistry and Affymetrix DNA array chip. The data were confirmed by western blot and further validated in human HCC tissues. Results: We observed an interesting biphase response pattern of lipid metabolomics in both HBx and pre-S2 mutant transgenic mice models of HBV tumorigenesis. The first peak of fatty change occurred in the early phase of 1-3 months, which subsided and then remarkably increased or terminally switched in HCC tissues. This biphasic pattern was synchronized with ATP citrate lyase (ACYL ) activation, followed by the activation of sertol regulatory element binding transcription factor 1 (SEBPF1) and fatty acid desaturase 2 (FADS2) in pre-S2 model. In HBx model, five lipid genes were specifically activated at the terminal phase including the lipoprotein lipase, fatty acid binding protein (FABP). In both models, the endoplasmic reticulum (ER) stress-induced mTOR pathway is the driving signals. Such an ER stress-dependent mTOR signal cascade is also important for cell proliferation of hepatocytes and further validated in HCC tissues. Conclusion: The mTOR signal pathway is important for the lipid metabolic disorders and the driving force for HBV tumorigenesis in animal and human models. To target on this pathway we will provide chemoprevention for HCC tumorigenesis in high risk patients of chronic HBV infection.
Chang Gong
Sun Yat-Sen University,China
Title: BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10
Time : 14:50-15:10
Biography:
Dr. Chang Gong has completed her MD in 2004 and PhD in 2010 from Sun Yat-Sen University as well as postdoctoral studies from INSERM, France. She is an associate professor of breast surgery in Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University. She focuses on the mechanisms of drug resistance and metastasis of breast cancer. She has published 15 papers in reputed journals.
Abstract:
BRMS1L (breast cancer metastasis suppressor 1 like，BRMS1-like) is a component of the SIN3A-HDAC corepressor complex that suppresses target gene transcription. However, the contribution of BRMS1L in cancer development is not well characterized. Here, we show that reduced BRMS1L in breast cancer tissues is associated with tumor metastasis and poor patient survival. Functionally, BRMS1L inhibits migration and invasion of breast cancer cells by inhibiting epithelial-mesenchymal transition (EMT). These effects are mediated by epigenetic silencing of FZD10, a receptor for Wnt signaling, by facilitating the recruitment of HDAC1 to its promoter and enhancing histone H3K9 deacetylation. Consequently, BRMS1L-induced FZD10 silencing inhibits aberrant activation of WNT3-FZD10-ï¢-catenin signaling. Furthermore, BRMS1L is a target of miR-106b and miR-106b upregulation leads to BRMS1L reduction, which is responsible for Wnt pathway activation and the ensuing EMT in breast cancer cells. RNAi-mediated silencing of BRMS1L expression promotes metastasis of breast cancer xenografts in immunocompromised mice, while ectopic BRMS1L expression inhibits metastasis. Therefore, BRMS1L provides an epigenetic regulation of Wnt signaling in breast cancer cells and acts as a breast cancer metastasis suppressor.
Houkai Li
Shanghai University of Traditional Chinese Medicine, China
Title: Combined metabolomic and transcriptomic profiling revealed the time-dependent effects of metformin on LoVo cells
Time : 15:30-15:50
Biography:
Houkai Li has completed his PhD at the age of 32 years from Shanghai Jiao Tong University and Postdoctoral studies from University of North Carolina (2011.8-2013.5) and Chinese Academy Sciences (2008.11-2011.3) respectively. He is now a Professor at Center for Traditional Chinese Medicine and Systems Biology in Shanghai University of Traditional Chinese Medicine. He has published over 22 papers in reputed journals.
Abstract:
Metformin is a commonly used anti-diabetic drug, which has been recognized of possessing potential anticancer activities in a variety of cancer models. However, the exact mechanism is poorly understood. In current study, we performed a GC-TOFMS and LC-TOFMS-based metabolomic profiling on LoVo cells, a human derived colon cancer cell line, treated by 10 mM metformin for 8, 24 and 48h respectively. Although the significant suppression on cell viability was only observed after 24h treatment, an obvious metabolic alteration was present after 8h treatment, and these metabolic changes were further amplified after 24 and 48h metformin treatment in consistence with the time-dependent suppressive effects on cell viability. Nevertheless, we observed that most differential metabolites were up-regulated at 8h, but down-regulated at 24 and 48h by metformin compared to the corresponding control cells, indicating the different modulation in cell metabolism by metformin at different time points. We found that most of the identified differential metabolites were involved in amino acids metabolism, glycolysis, TCA cycle, and nucleic acids metabolism, suggesting that the metabolic impacts of metformin on energy metabolism were prior to the phenotypic changes in cell viability. Meanwhile, we performed a transcriptomic profile of LoVo cells which were treated by 10mM metformin for 8 and 24h. The transcriptomic data showed there are over 100 and 3000 differentially expressed genes induced by 8 and 24h metformin treatment compared to the corresponding control cells. Interestingly, we found that the impacts of normal 24h culture were greater than 8h treatment of metformin on gene expression, which was different with the observed metabolic alterations. We observed that the main involved pathways of differentially expressed genes were not only related with classical cancer signaling pathways such as Wnt signaling, p53 signaling, MAPK pathway, cell cycle, apoptosis and ErbB signaling pathway, but also with energy metabolism process. Altogether, our current data indicate that metformin treatment results in a time-dependent metabolic and transcriptomic alteration on LoVo cells, and the results from these two omics approaches could be complementary and warrants a further investigation on these observed changes of genes and metabolic pathways.
Xiaoyan Wang
Shanghai Center for Systems Biomedicine, China
Title: Metabolomics approach to understanding the metabolic regulatory effects on rats under several kinds of stresses
Time : 15:50-16:10
Biography:
Xiaoyan Wang got her PhD in Pharmacology from Shanghai Jiao Tong University and now is an Associate Professor at the Shanghai Center for Systems Biomedicine. She has been engaged in stress related metabolomics and pharmacology study and has published more than 20 papers in reputed journals
Abstract:
Stress may trigger systemic biochemical and physiological changes in living organisms, leading to a rapid loss of homeostasis, which might cause further tissue injury and could also be gradually reinstated when stress source was removed. However, such a sophisticated metabolic regulatory process has so far been poorly understood, especially from a holistic view. The series of metabolomics analysis on urine, serum and tissue samples derived from rat models of acute cold stress, forced swimming stress, Chronic Unpredictable Mild Stress (CUMS) and subacute heat stress enables us to visualize significant alterations in metabolite expression patterns as a result of stress-induced metabolic responses and post-stress compensation. The results indicate the mild and acute stress, like cold and forced swimming stress induced metabolic perturbations were reversible and nonspecific, but long-term stress, as subacute heat and chronic, unpredictable mild stress, brought sustained metabolic distributions and caused more injury to other tissues including brain (CUMS) and testicles(heat stress). The differentially expressed metabolites were involved in metabolic regulation and compensation required to restore homeostasis, especially in the epididymis, metabolites with reproductive benefits were found being up-regulated to play a self-protective function in resisting, heat stress and to maintain normal reproductive function. Meanwhile, our study provides a dynamic and systemic approach for the characterization of anti-stress and metabolic protective effects of ginsenosides from the herbal drug named Ginseng
Fuxiang Zhou
Zhongnan Hospital of Wuhan University, China
Title: Title: Mitochondrial DNA depletion in H1299 cells promotes radio-resistance and anti-apoptosis through activation of PI3K/Akt2
Time : 16:10-16:30
Biography:
Fuxiang Zhou has completed his Ph.D at the age of 40 years old from Zhongnan Hospital of Wuhan University and postdoctoral studies from CAL Cancer Center, University of Nice, France. He is the director of Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center. He has published more than 60 papers in reputed journals and serving as an editorial board member of repute.
Abstract:
Radiotherapy takes an important role in treatment of various cancers while the main limit for this strategy is radioresistance of cancer cells. A large number of studies have found that mitochondrial DNA (mtDNA) is not only associated with tumor development, but also affect the tumor radiosensitivity. But, the roles of mtDNA on radiosensitivity are still conflictable, and the mechanisms remain unresolved. Here, we have built a cell model with mtDNA deletion, to investigate the relationship between mtDNA and radiosensitivity and its mechanism. Human non-small cell lung cancer cells (H1299) were depleted of mtDNA (ρ0) by culturing chronically in the presence of ethidium bromide, and then verified by PCR of total DNA using primer pairs specific for mtDNA. We found that loss of mtDNA decreased proliferation rate, ATP and oxidative phosphorylation. Moreover, ρ0 cells regulate radio-sensitivity: (a)by inhibiting cell cycle progression at the G2/M transition leading to growth arrest and apoptosis; (b) by increasing the expression of G2/M checkpoint ATM/ATR-mitotic cyclinB1 and decrease the expression of apoptotic factors pro-caspases-3 and -8; and (c) accelerated the repair kinetics of DNA damage induced by irradiation. We further examined the phosphorylation of Akt2, mTOR and IKKs and found they all were significantly increased in ρ0 cells. In keeping with these findings, suppression of the PI3K/Akt2 pathway by the small molecular inhibitor MK-2206 2HCL dramatically increased the expression of apoptotic proteins in ρ0 cells. Collectively, our results indicated that mtDNA depletion resulting in downregulation of radiosensitivity, and retrograde activation the PI3K/Akt2 pathway in non-small cell lung cells.
Jayaraman G
VIT University, India
Title: Comparative metabolic profiling of halotolerant bacterial strains and identification of novel species-specific metabolites
Time : 16:30-16:50
Biography:
Jayaraman G obtained his PhD degree at the National Tsing Hua University (Taiwan) in Structural Biology in 1998 and continued as a Post-doctoral Fellow with funding from National Health Research Institute, Taiwan. Though continuing to explore the structure-function relation of snake venom proteins, he has expanded his interest in understanding the adaptative features of halotolerant organisms. Currently, he is a professor at VIT University (India) and has more than 75 research articles published in international journals.
Abstract:
The salt stress response of four representative halotolerant bacterial species (Halomonas hydrothermalis VITP9, Bacillus aquimaris VITP4, Planococcus maritimus VITP21 and Virgibacillus dokdonensis VITP14) isolated from a previously unexplored solar saltern in Kumta, along the Arabian Sea coast in Karnataka, India was analyzed using comparative metabolomics approach. Chemometric analysis of 1H NMR spectra revealed salt-dependent increase in the levels of metabolites, mainly from the aspartate and glutamate family, that are directed from the glycolytic pathway, pentose phosphate pathway and citric acid cycle. The composition of the metabolites was found to be different with respect to the species and the type of growth medium. Two dimensional NMR data revealed accumulation of two rare diaminoacids, Nε- acetyl-α-lysine and Nδ-acetylornithine apart from other well known compatible solutes. Metabolite profiles of species capable of synthesizing Nε-acetyl-α-lysine and Nδ-acetylornithine suggested their biosynthesis from lysine and ornithine using aspartate and glutamate as their precursors, respectively. One of the species, Planococcus maritimus VITP21 was found to accumulate an unusual sugar, (2-acetamido-2-deoxy-α-D-glucopyranosyl)-(1→2)-β-D-fructofuranose is not previously reported for its natural synthesis by any other organism. The protective effects of Nε-acetyl-α-lysine and (2-acetamido-2-deoxy-α-Dglucopyranosyl)-(1→2)-β-D-fructo furanose along with other commonly occurring bacterial osmolytes, ectoine, proline, sucrose, trehalose and glycine betaine on protein stability and activity were evaluated with a few of possible biotechnological application.
Cocktails sponsored by Journal of Metabolomics: Open Access 18:15-19:15 @ Independence Foyer