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S PRESENTED Metabolic Regulation of Tumor Microenvironment Heterogeneity G. G. Xiao. School of Pharmaceutical Science, Dalian University of Technology, Dalian, China; Creighton University Medical Center, Omaha, NE. Background: Tumor Microenvironment is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules and the extracellular matrix. The tumor microenvironment contributes to tumor heterogeneity. Exact mechanism of causing tumor heterogeneity is not clearly understood yet. Results and Discussion: Data from our previous research and others suggest that tumor heterogeneity may be resulted from unsynchronized differentiation of cancer progenitor cells. We then hypothesized that cell phenotype may be altered by proteome phenotype that is resulted from altered genomic phenotype that may be regulated by metabolic phenotype initiated by early signals. In another words, heterogeneity of tumor microenvironment may be resulted from dysregulated metabolic phenotypes. To test our hypothesis, we developed analytical methods to measure quantitatively the signals and its initiated metabolic phenotypes in a cell. The methods developed in our group at both UCLA and Creighton University include stable isotopomer-based flux analysis and dynamic measurement of protein turnover in a cell, which extensively used in cancer research. In this oral communication, the details on how Pancreas • Volume 47, Number 5, May/June 2018 Pancreas • Volume 47, Number 5, May/June 2018 Conference Report these methods can be used will be delivered and an example based on the methods will be also illustrated. Conclusion: Understanding the mechanism underlying tumor microenvironment heterogeneity regulated metabolically is key for development of anticancer drugs with minimum toxicity and maximal effectiveness. Ubiquitylation of Autophagy Receptors: Multiple Modes of Regulation on Cellular Autophagic Flux R. Hu. State Key Lab of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), Shanghai, China. Background: Ubiquitin (Ub) signaling regulates myriad of fundamental cellular activities. The alterations in cellular Ub homeostasis, known as Ub stress, feature and affect cellular responses in multiple conditions, yet the underlying mechanisms are incompletely understood. Method: By biochemical and cell biologymethodwe found that p62/SQSTM1 was polyubiquitylated inUb+ stress conditions, andwe identified its E2 enzyme Ube2d2 and Ube2d3 in yeast two hybrid screening, then we mapped the E2-dependant ubiquitylation sites by mass spectrum analysis. We further confirmed that polyubiquitylated p62 form large complex than unmodified p62 by electro-microscopy and dynamic light scattering analysis. Results: Ub+ stress in cells induced by over-expression of Ub, prolonged proteasomal inhibition and heat shock could efficiently induce autophagy in dependence of autophagy receptor, p62/SQSTM1, p62 was increasingly ubiquitylated during those conditions. Subsequently, p62 was found to specifically interact with two Ub conjugating enzymes, Ube2d2 or Ube2d3, using a common E2-interacting region (EIR), and these E2s could support p62 ubiquitylation both in vitro and in the cell. Multiple Lys (K) residues in p62 were mapped as the sites for this E2-supported ubiquitylation, which include K420 in the UBA domain of p62. As previously reported, UBA domains in p62 formed stable dimers, which would prevent p62 from binding to polyUb chain in autophagy cargos; our in vitro polyUbbinding data showed that polyubiquitylated p62 in the presence of the E2s bind to polyUb chains much more efficiently than unmodified p62. Consistently, electro-microscopy and dynamic light scattering analyses indicated that polyubiquitylated p62 might predominantly form large complex with polyUb chains (~ two fold lager in diameter) than unmodified p62, suggesting that p62 might have indeed adopted an open conformation upon E2-supported polyubiquitylation. Conclusion: By discovering E2-supported ubiquitylation of p62 as a novel mechanism for activating its autophagy receptor function under Ub+ stress conditions, our work has thus revealed a unique “sensor” function of p62 in modulating autophagy as part of the cellular responses to prolonged proteasomal inhibition, heat shock or Ub overexpression. Identifying Clinically Actionable Alterations in the Era of P4plus Medicine: Challenges and Opportunities B. Shen. Center for Systems Biology, Soochow University, Suzhou, China. Background: The Chinese government recently launched two projects, i.e. “Healthy China 2030” and "Genetic testing for Chinese public health: science and social engineering". The programs center on chronic disease prevention and promoting personalized and positive lifestyle choices. Scientifically the identification of actionable alterations in gene, lifestyle or environmental factors will be the key for the diagnosis and prognosis of diseases and the improving of population healthcare. Method: I will present our researches on the identification of actionable biomarkers for diagnosis of complex diseases and talk about our strategies for the biomarker discovery from big data to small data, based on the statistical analysis of the reported biomarkers, the mechanistic and functional analysis of biological networks. Results: We first studied the network properties of gene society, and then applied the ideas to the identification of microRNA biomarkers for cancers, such as prostate cancer and leukemia. We cooperated with medical doctors to verify our findings by collect disease samples and experimental confirmation. Conclusion: The future challenges and opportunities for the P4 medicine, i.e. predictive, preventive, personalized and participatory medicine include the data privacy, lifestyle, universal and experimental data characterization as well as the standardization of diverse unstructured data. © 2018 Wolters Kluwer Health, Inc. All rights reserved. The Role of Hypermethylated in Cancer 1 (HIC1) in Tumorigenesis and Development M. Hao, Y. Wang, X. Weng, J. Wang. Department of Biochemistry and Molecular & Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH; Fudan University Shanghai Cancer Center, Shanghai, China. Background: Hypermethylated in cancer 1 (HIC1) is a tumor suppressor gene and a transcriptional inhibitory factor, whose promoter is usually silenced in many solid tumor tissues and precancerous lesions (such as smokers’ lung, colorectal polyps and other tissues). HIC1+/mice studies also suggest that the gene may be associated with tumorigenesis, tumor development and metastasis. Method: Avariety of solid tumor tissues (including prostate cancer, breast cancer, lung cancer, etc.) were collected for analyzing HIC1 expression and methylation status. In vitro and in vivo (HIC1 cKO and transplant mice model) experiments were utilized to study the phenotypes as well as mechanisms upon HIC1 loss or reexpression. Results: In recent years, our team have conducted a series of studies on HIC1 and found that hyper methylation of HIC1 promoters in a variety of solid tumor tissues (including prostate cancer, breast cancer, lung cancer, etc.) may lead to HIC1 silence, resulting in suppressive function loss or attenuation in these tumors. In vitro and in vivo experiments show that the recovery of HIC1 expression could significantly reduce the tumor proliferation, invasion, and metastasis. Mechanism studies disclose that HIC1 expression is widely modulated including ubiquitination, SUMOylation, as well as methylation. Conclusion: These studies suggest that HIC1 may act as a potential tumor biomarker, which provides new ideas for the early diagnosis and treatment of tumors. RP-MDM2-p53 Pathway Regulates Lipid Metabolism and Acts as the Checkpoint of Myc-induced Lymphomagenesis Y. Liu, E. Macias, Y. Zhang. Cancer Institute, Xuzhou Medical University, Xuzhou, China. Background: The tumor suppressor p53 has recently been shown to regulate lipid metabolism through multiple mechanisms. However, the in vivo signaling pathways related to p53-mediated metabolic regulation remain largely uncharacterized. Results: By using mice bearing a single amino acid substitution at cysteine residue 305 of mouse double minute 2 (Mdm2), which renders Mdm2 deficient in binding ribosomal proteins (RPs) RPL11 and RPL5, we show that the RP–Mdm2–p53 signaling pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis. Nutrient deprivation inhibits rRNA biosynthesis and triggers ribosomal stress, which increases RP–Mdm2 interaction, and induces p53-mediated transactivation of malonyl-CoA decarboxylase (MCD), leading to increased fatty acid oxidation. By contrast, Mdm2 mutant mice demonstrate attenuated MCD induction and increased lipid accumulation in the liver. Furthermore, to test whether RP-Mdm2-p53 pathway involved in the tumor suppressive function of p53, we crossed Mdm2 mouse with Eμ-myc mouse, and found that interruption of RP-MDM2 interaction strikingly accelerates oncogenic Myc-induced lymphomagenesis. Conclusion: Thus, the RP–Mdm2–p53 pathway appears to function as an endogenous stress sensor responsible for breaking down lipid storage for survival. However, in response to oncogene over-activation, this pathway acts as the checkpoint of excessive ribosome biogenesis. miR-1207-5p Induced Metastasis by Regulating Tryptase-alpha-1 in Oral Cancer M. Cao, Q. Yang, X. Miao, J. Liu, Y. Pan, G.G. Xiao. School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China. Background: Oral cancer metastasis is a life threatening health problem worldwide. Development of an effective strategy for treatment of oral c

Proceedings of the 2nd International Conference for Cancer Metabolism and Therapy, October 13–15, 2017, Wenzhou, China