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2012 Systems biology in the frontier of cancer research: a report of the Second International Workshop of Cancer Systems Biology Juan Cui University of Georgia, [email protected]

Yan-Chun Liang Jilin University

Ying Xu Jilin University, [email protected]

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Cui, Juan; Liang, Yan-Chun; and Xu, Ying, "Systems biology in the frontier of cancer research: a report of the Second International Workshop of Cancer Systems Biology" (2012). CSE Journal Articles. 183. http://digitalcommons.unl.edu/csearticles/183

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Conference Report

Juan Cui 1, Yan鄄Chu n Liang 2 and Ying Xu 1,2

Abstract The report summarizes the Second International Workshop of Cancer Systems Biology held on July 5-6, 2012 in Changchun, China. The goal of the workshop was to bring together cancer researchers with different backgrounds to share their views about cancer and their experiences in fighting against cancer, and to gain new and systems鄄leve l understanding about cancer formation, progression, diagnosis, and treatment through exchanging ideas.

The Second International Workshop of Cancer and techniques to treat cancer patients. Having such a Systems Biology (ICSB) (http://ccst.jlu.edu.cn/icsb2012/), diverse group of people speaking to each other and to hosted by Jilin University, was held from July 5 to 6, an audience with an even wider range of expertise 2012 in Changchun, China. During this two­day meeting, generated much excitement. At the end of the meeting, 21 invited speakers, 7 from China, 13 from the United virtually all speakers and many attendees expressed States, and 1 from Canada, gave speeches covering a praise for the workshop as one of the best they had wide range of topics on cancer systems biology to an attended, having been impressed by the overall quality of audience of approximately 300 people from across the talks and the intellectual level of the dialog it created. China. The 21 talks roughly fell into four categories: This meeting, which is the second in its series, was cancer genome analysis and information discovery, initiated by Professor Ying Xu (University of Georgia and cancer mechanism studies, biomarker discovery, and Jilin University) and Professor Yan­Chun Liang (Jilin cancer treatment strategies. By design, these talks were University) in early 2011. The overall consideration in delivered by cancer researchers and practitioners with organizing this annual meeting is to bring together diverse backgrounds who may not otherwise have cancer researchers with different backgrounds to share opportunities to meet and share their visions about their views and experiences in fighting cancer and to cancer studies in an open and scientifically stimulating gain new systems­level understanding of cancer environment. Among the speakers were cancer formation, progression, diagnosis, and treatment through biologists who study specific cancer pathways, exchanging ideas. Professor Liang Hu, Dean of the computational cancer biologists who rely on large­scale College of Computer Science and Technology at Jilin data for global information discovery, computational University, generously agreed to financially sponsor the modelers who examine dynamic properties of cancer, first three annual meetings of this series, which has immunologists who study cancer in a larger context than made this and the previous meeting possible. Like in the just tumors, and clinicians who use different strategies first meeting in 2011, the organizers felt very fortunate for the opportunity to bring together this group of leaders in their respective research areas to present their science and lead discussions. 1Comp utational Systems Biology Laboratory, Depart鄄 ment of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602 -7229, USA; 2Col lege of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P. R. China. Cancer Genome/Epigenome Sequencing Ying Xu, Computational Systems Biology Laboratory, and Information Discovery Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602-7229, USA. Tel: +1鄄70 6鄄54 2鄄977 9; Fax: +1鄄706 鄄542 鄄 To understand the genetic basis of cancer, two large 9751; Email: [email protected]. cancer genome sequencing projects have been initiated: 10.5732/cjc.012.10圆05 one by the International Cancer Genome Consortium

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and the other by the US National Cancer Institute and almost all types of cancer. Dr. Dong Xu (University of National Human Genome Research Institute, named The Missouri) described his group s bisulfite­sequencing Cancer Genome Atlas (TCGA). TCGA aims to develop a analysis of DNA methylation patte爷 rns across different complete atlas of all genomic alterations involved in cancer tissue samples. They identified digital profiles of dozens o f 野major冶 cancer types. Dr. Wei Zhang (MD aberrant DNA methylation and suggested potential Anderson Cancer Center), a principal investigator of the methylation biomarkers for cancer subtypes. They also TCGA Initiative, presented a study by his group on the studied sequence and methylation patterns among DNA implications of and mutations on ovarian methyltransferases and found long­range patterns in the cancer prognosis. They found that ­mutated flanking sequences around methylation sites and ovarian cancers have higher levels of gene mutations, cooperativity among different DNA methyltransferases. In respond better to front­line therapy, and have a longer addition, they found that DNA methylation in the 3'­UTR overall and progression­free survival. In addition, he also was positively correlated with expression of the upstream discussed their recent genome sequencing study of gene, in contrast to negative correlation of expression colorectal cancer, which was published in the July 2012 with its promoter region. Their analysis indicates that 3'­ issue of , as well as their bioinformatic analyses UTRs are hypomethylated in tumor samples and that on endometrial cancer that revealed three distinct genes with longer 3'­UTRs tend to have more differential subtypes with distinct pathway­ level characteristics. methylation and thus a higher ability to regulate the gene Dr. Juan Cui (University of Georgia) introduced her expression. group s recent study in which the whole genomes of five In addition, Dr. Wen­Yi Wang (MD Anderson Cancer gastric爷 adenocarcinomas and matching controls were Center) also presented her work on cancer genome sequenced. The density of the mutation spectrum of analyses and applications. each cancer genome ranged from 6.8 to 13.8 mutations per Mb of DNA. In total, 407 non­synonymous somatic point variations were identified, primarily occurring in Mechanisms of Cancer mucins and transcription factors. Seventy­six genes had copy­number changes, and 679 genomic rearrange Four talks were focused on mechanisms of cancer. 鄄 ments were detected. The study revealed that 79.6% of Speakers discussed the topic from their own unique the chromosomal rearrangements occurred among perspectives, some with a more traditional focus on neighboring regions in the folded chromosomes, based specific cancer­related pathways and others with a focus on mapping of the boundaries of the rearranged regions on global pictures. to the folded three­dimensional structures of the human Dr. Ying Xu (University of Georgia) presented a chromosomes and the replication timing profiles. model showing that hypoxia may serve as a key driver In his presentation, Dr. Jin­Tang Dong (Emory for cancer growth. The idea of the model is that as a cell University) demonstrated how a tumor suppressor gene becomes increasingly more hypoxic, there is a switch in can be identified from a chromosomal region that is cellular respiration from oxidative phosphorylation to frequently deleted in human cancer. Specifically, he and glycolysis, which was first reported 90 years ago by Otto his colleagues presented krueppel­like factor 5 (KLF5) as Warburg. Such a switch in energy metabolisms leads to a tumor suppressor gene based on and decreased generation of ATP per glucose and results in studies and reported a novel mechanism for how KLF5 increased glucose uptake by the affected cells, a can be inactivated in human cancer. Interestingly, animal phenomenon that is widely observed through cancer studies demonstrated that KLF5 can act as both a tumor imaging data. The increased accumulation of glucose is suppressor and promoter, and biochemical analyses of cultured epithelial cells revealed a possible mechanism due to the fact that the outgoing rates of carbons through for how KLF5 can switch functions. In their lactate and the electron transport chain are significantly studies, Dr. Dong s group found that KLF5 is a cofactor lower than incoming rates of carbons from the glucose. 爷 The accumulated glucose/intermediates must be cleared of TGF­茁 signaling, and TGF­茁­induc ed acetylation of KLF5 is the key event that reverses the function of or cells will die. Cells have evolved to adopt the process KLF5. In the absence of TGF­茁, KLF5 is not acetylated of biosynthesis to relieve this carbon burden, which and promotes cell proliferation by regulating cell cycle gradually leads to systematic changes in cellular genes. However, when TGF­茁 is present, KLF5 is metabolism and ultimately results in the synthesis of new acetylated and the acetylation reassembles the KLF5 cells. This cycle accelerates as the cell population transcriptional complex, leading to a change in gene becomes increasingly more hypoxic and forms a transcription and the reversal of KLF5 function. self­propelling cycle driven by the force to remove DNA methylation is associated with silencing or excess carbons. This model is consistent with the large­ overexpression of many biologically important genes in scale transcriptomic data.

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Evasion of apoptosis is one of the key hallmarks of signature by gene expression profiling. cancer and a major target of cancer therapy. Dr. Dr. Bing Zhang (Vanderbilt University) discussed his Shi­Yong Sun (Emory University) discussed death group s work on identifying prognostic markers for 爷 receptor 5 (DR5), a cell surface pro­apoptotic death colorectal cancer. They investigated eight published receptor for tumor necrosis factor­related apoptosis­ colorectal cancer gene expression signatures. Using a inducing ligand (TRAIL). Oncogenic mutations of Ras random walk­based approach, they integrated these and B­Raf frequently occur in cancer and are critical to signatures and publicly available somatic mutation data cell transformation and tumorigenesis. In their recent on a protein­protein interaction network and inferred 487 study, Dr. Sun and colleagues forced expression of genes as plausible candidate molecular underpinnings oncogenic Ras or B­Raf and demonstrated that for the colorectal cancer recurrence phenotype. The these proteins positively regulate DR5 expression. This resultant list of genes was deemed an NEM signature. finding is further supported by results showing that An NEM signature­based survival support vector knockdown of endogenous K­Ras or B­Raf reduced the machine prognostic model was trained using a gene expression of DR5. Importantly, they also showed that expression dataset and tested on an independent Ras induced DR5 expression through co­activation of the dataset. The model­based scores were 75.7% ERK/RSK and JNK signaling pathways and subsequent concordant with patient survival data and separated patients into two groups with significantly different cooperative effects among the transcriptional factors relapse­free survival ( = 0.002). Furthermore, adjuvant CHOP, Elk1, and c­Jun. chemotherapy was significantly associated with In addition, Dr. Zhiren Luis Liu (Georgia State prolonged survival of the high­risk patients ( = 0.006) University) and Dr. Xiaole Shirley Liu (Harvard University but not beneficial to the low­risk patients ( = 0.491). and Dana­Farber Cancer Institute) also presented their Thus, the NEM signature not only reflects colorectal work. cancer biology but also informs patient prognosis and treatment response. Search for Biomarkers for Cancer The other biomarker talks were focused on existing techniques for biomarker identification. For example, one Subtyping, Diagnosis, and Prognosis major problem is that most biomarkers cannot be There were six talks on the identification and reproducibly identified by independent studies. To application of biomarkers. Dr. Ya­Ping Tian (Beijing 301 address this, Dr. Zheng Guo (Harbin Medical University) Hospital) described his group s study of the peripheral proposed a new strategy of using scores to evaluate the blood from which they identif爷ied an 8­gene panel that functional reproducibility of cancer biomarkers based on could be used to distinguish blood samples of hepatitis molecular models that take into account the functional B, liver cirrhosis, and hepatocellular carcinoma patients associations among the marker genes/proteins. The from those of healthy donors with high statistical biological assumption underlying a score is statistically significance. Based on this study, they have developed a testable to explain the diverse but functionally related peripheral blood gene expression profiling test (GeXP) biomarker genes/proteins. Dr. Guo reported that for differential diagnosis of hepatic diseases. biomarkers identified using this method could be Dr. Chao­Nan (Miles) Qian (Van Andel Research reproducibly detected when using different omic Institute and Sun Yat­sen University Cancer Center) datasets. presented his team s finding that the secreted molecules Another serious issue is that while both molecular serglycin and interleuk爷 in­8 (IL­8) promote metastasis of and network biomarkers can be used to distinguish nasopharyngeal carcinoma (NPC) cells through autocrine disease samples from normal samples, neither are and paracrine mechanisms and serve as independent guaranteed to successfully identify pre­disease samples prognostic factors for the survival of NPC patients. They due to their static nature. Thus, these markers are not found that IL­8 can induce the expression of many useful for early diagnosis. In a departure from traditional mesenchymal markers and suppress the expression of approaches, Dr. Luo­Nan Chen (Chinese Academy of epithelial markers. Clinically, cancer cells with a high Sciences, Shanghai) has recently developed a new propensity for metastasis are the primary cause of theory of dynamical network biomarkers (DNBs) based patient death. However, these cells may be present in on nonlinear dynamical theory and network theory. very low numbers in primary tumors, hence making gene Applying this theory, Dr. Chen and his research team expression profiling a major challenge. Therefore, as Dr. showed for the first time that DNBs can distinguish the Qian s group demonstrated through their studies, using pre­disease state from the normal state, even with small parenta爷 l cells to isolate metastatic clones may be a numbers of samples, and therefore have a great useful strategy to overcome this challenge and allow potential to achieve real early diagnosis of complex 野 冶 identification of the pro­metastatic gene expression diseases like cancer.

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Dr. Edwin Wang (National Research Council Canada eradicated the directly injected melanoma tumors but and McGill University) showed that alterations of tumor also caused regression of collateral melanoma tumors in suppressor genes are essential to cancer development 2 out of 19 patients with in­transit melanoma in a phase I and progression. Mutation of tumor suppressor genes trial by Adil Daud. Dr. Shu­Lin Li (MD Anderson Cancer often increases genomic instability, which makes Center) reported that he and his colleagues generated a passenger, or non­specific, signals more common in tumor­targeted IL­12 that is more effective than wild­type tumor cells than in other cell types and causes variability IL­12 in inhibiting metastatic tumors. He also showed in the gene expression profiles between individual results of their study in which the IL­12 gene and tumors. Thus, the real cancer gene expression signals chemical medicine were co­administered via may be buried in 野 these冶 highly varied profiles. These electroporation to treat recurrent and large­volume insights prompted Dr. Wang and colleagues to develop a squamous cell carcinoma in dogs. The central hypo 鄄 new algorithm that focuses on functional modules thesis behind this co­administration approach is that instead of network modules, which are limited by a lack chemotherapy delivered by electroporation will cause of comprehensive network data. These functional tumor cell death and release of tumor antigens, while modules provide several advantages as they (1) reduce IL­12 gene therapy delivered by electroporation will potential passenger signals; (2) overcome the well­ recruit and stimulate immune cells to process the known over­fitting problems; and (3) make the effects of released antigens to generate an antitumor immune the biomarkers more stable due to the functional memory. The success in causing tumor regression in interactions between the genes in a functional module. dogs provides solid evidence to support this hypothesis. As proof­of­concept, they successfully applied the Dr. Ya­Jun Guo, Dr. Xiao­Ning Wang, and Dr. Ying algorithm and identified breast cancer prognostic Gu, all from Beijing 301 Hospital, also presented their biomarkers that could identify low­risk patient in eight experience in treating cancers using different techniques independent cohorts containing more than 1300 patients. and strategies. Dr. Shyr Yu (Vanderbilt University) also presented a talk about issues with the existing methods commonly used in bioinformatics studies and offered new solutions. Concluding Remarks

Forty years have passed since the declaration of Drug Targets and Cancer Treatment the war on cancer in the early 1970s. While Strategies cons idera野 ble progress 冶has been made in our overall ability to fight this disease, cancer remains the second In his talk, Dr. Wei­Ping Zou (University of leading cause of death worldwide. The reality is that we Michigan) focused on Th17 cells in the tumor are still far from reaching the goal set 40 years ago. The microenvironment. Th17 cells phenotypically resemble to general consensus in the field has been that terminally differentiated memory T cells, but are different fundamentally new ways to study cancer should be from central memory, exhausted and senescent T cells. developed based on the lessons learned in the past. We His group demonstrated that Th17 cells mediate and aimed to use this meeting series to bring together promote long­term antitumor immunity. Furthermore, researchers who have been studying cancer from very Th17 cells have stem cell­like features including high different perspectives to develop novel views, ask deeper capacity of proliferative self­renewal, potent persistence questions about the essence of cancer, and generate and apoptotic resistance , and the generation of new dialogs/collaborations leading to fundamentally new other types of T helper cells. Moreover, the stem cell­like understanding about cancer at the systems level. characteristics of these cells are regulated by the signaling pathways of hypoxia­inducible factor 1琢 (HIF1琢) and Notch. Thus, Th17 cells may be a long­lived proliferating T cell population with stem cell charac Acknowledgments teristics, which may be important determinants in Th17 鄄 We thank the College of Computer Science and biology. Therefore targeting the Th17 stemness would be Technology of Jilin University and the National Science therapeutically meaningful for treating patients with Foundation of China for their funding support of the ICSB chronic diseases affected by Th17 cells meeting series. Electroporation is becoming a powerful and yet very simple drug delivery tool for cancer treatment. Received: 2012­08­08; accepted: 2012­08­17. Administration of DNA encoding IL­12 has not only

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