Costas Lyssiotis, PhD
Assistant Professor of Molecular & Integrative Physiology
Assistant Professor of Internal Medicine
[email protected]

Shigang Ding, MD
丁士刚教授
Professor and Director
Department of Gastroenterology
Peking University Third Hospital

JI Program: Liver and GI Disease

Project Status: Active/Ongoing

Gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDA) are a major cause of mortality in China and the United States. A primary reason for this is the lack of effective therapeutic options. Thus, there is an urgent need to develop new drug targets. Metabolism is rewired in these cancers to support the demands of dysregulated cellular proliferation and tumor growth. Accordingly, tumor metabolism has emerged as a promising therapeutic inroad. Work from the Lyssiotis (University of Michigan) and Ding (Peking University) laboratories have independently demonstrated the potential of Malic Enzyme 1 (ME1) as a novel metabolic drug target in pancreatic and gastric cancer, respectively. In this collaborative project, our groups will continue our productive international collaboration by further defining the role of ME1 in cancer (mechanism of action), determining the genetic context to target ME1 (precision medicine), and determining the safety profile of ME1 inhibition. Notably, this proposal combines the expertise in cancer metabolism, preliminary data, and a wealth of novel ME1 reagents/tools from the Lyssiotis lab with the expertise in gastrointestinal disease and access to a unique patient cohort and biobank of GC specimens in the Ding lab. We are extremely excited for the opportunity to work together with the PUUMA program and look forward to developing a new metabolism targeted therapy for pancreatic and gastric cancer.

Elizabeth Speliotes, MD, PhD, MPH
Associate Professor of Computational Medicine and Bioinformatics
Associate Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Linong Ji, MD
纪立农教授
Professor of Medicine, Department of Endocrinology and Metabolism
Deputy Director, Peking University Gerontology Center
Co-director, Peking University Diabetes Center
Peking University Health Science Center
[email protected]

JI Program: Liver/GI

Active/Ongoing

Nonalcoholic fatty liver disease has increased with the rise of obesity and can contribute to liver and cardiometabolic disease. We identified genetic subtypes of NAFLD and environmental causes of NAFLD in genetically predisposed individuals. This work was mostly performed in individuals of European ancestry. Individuals of Asian ancestry have higher rates of metabolic disease including NAFLD controlling for obesity than individuals of European ancestry. Whether this is genetically or environmentally mediated is not known. Further, microbiota have been shown to influence obesity and NAFLD in small populations but their effect in large populations is not known. Here we collected a large well characterized population based cohort from Pinggu China where there is an explosion of metabolic disease. We have excellent measures of NAFLD, DNA, stool and a wealth of covariates. We now aim to genotype the cohort, carry out metagenomic analyses from stool, and collect follow up data on incident liver and cardiometabolic disease. We will then carry out analyses to define genetic and microbiome influences on prevalent NAFLD as well as the effect of NAFLD and its precipitants on incident liver and cardiometabolic disease. Results from this work will define genetic and environmental causes of NAFLD to help further refine treatments and precision care of patients with NAFLD.

Clifford Cho, MD, FACS
C Gardner Child Professor of Surgery and Professor of Surgery
University of Michigan Medical School
[email protected]

Yuan Hong, MD, PhD
洪源教授
Professor
Peking University First Hospital
[email protected]

JI Program: Cancer

Status: Active/ Ongoing

Project Summary

Hepatocellular carcinoma (HCC) is an aggressive malignancy whose poor prognosis is driven
in part by a lack of curative treatment options. We previously cloned three novel HCC-specific
murine T cell receptor (TCR) genes that can redirect human T cells to effectively eliminate HCC
tumor cells, demonstrating the potential to engineer a patient’s autologous T cells to treat HCC.
In addition, we have isolated specific CD8+ tumor infiltrating lymphocytes (TILs) from HCC patients
and observed their potent antitumor function after in vitro proliferation. In this project, we seek
to infuse CD8+ TILs derived from HCC patients into immunodeficient mice harboring autologous
HCC, and subsequently clone TCR genes from patient-derived CD8+ T cells with antitumor
phenotype. Following validation of their functions, we will determine their targeted tumor antigens
through epitope prediction algorithms and unbiased screening using yeast-display libraries.
In sum, we will identify novel tumoricidal TCR genes from HCC CD8+ TILs, thereby engineering
patient-derived autologous T cells to generate potently tumoricidal TCR-T lymphocytes to treat
HCC patients.

Yongqun (Oliver) He, PhD
Associate Professor, ULAM
Microbiology and Immunology
University of Michigan Medical School
[email protected]

Jianmin Wu, PhD
吴健民教授
Director, Center for Cancer Bioinformatics
Peking University Cancer Hospital
[email protected]

JI Program: GI & Liver

Status: Active/ Ongoing

Summary

Gastric cancer is the fifth most prevalent malignancy and the third leading cause of cancer death worldwide. Almost a half of new cases of gastric cancer occurred in China, where it is the second leading cause of cancer death. The strongest risk factor for gastric cancer is chronic Helicobacter pylori infection. People with H. pylori infection have a roughly six-fold greater risk of developing gastric cancer than uninfected people. However, not all people infected with H. pylori will develop gastric cancer, suggesting more factors and mechanisms involved in gastric carcinogenesis. We hypothesize that complex interactions between host genetic susceptible factors, H. pylori, and other gut microbes influence the host molecular and cellular activities, leading to the development of gastric cancer. Our study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis, with ex vivo verification using organoid models. This systematic study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis and provide proof-of-concept ex vivo experimental verification using organoid models, leading to further understanding of gastric carcinogenesis.

Thomas Wang, MD, PhD
H. Marvin Pollard Collegiate Professor of Endoscopy Research
Professor of Internal Medicine, Biomedical Medicine, and Mechanical Engineering
University of Michigan
[email protected]

Jiye Zhu, MD
朱继业教授
Director, Department of Hepatobiliary Surgery
Peking University People's Hospital

JI Program: GI & Liver

Status: Active/ Ongoing

Summary

We aim to leverage 8 years of collaboration between Dr. Thomas Wang at Michigan Medicine and Dr. Jiye Zhu at PKUHSC to identify, optimize, and validate a peptide-based targeting ligand specific for hepatocellular carcinoma (HCC).  A prototype medical laparoscope will be adapted to demonstrate proof-of-concept for image-guided surgery.  The peptide will be labeled with a near-infrared fluorophore to generate fluorescence in a spectral regime that can pass through several centimeters of tissue.  Peptides are small in size and low in molecular weight, thus offer a number of pharmacokinetic advantages for improved distribution in solid tumors, including deeper penetration, greater extravasation, and faster diffusion.  In addition, peptides have superior vascular permeability, better circulatory clearance, and reduced background levels.  If rigorously validated, this novel targeting moiety can be used for a number of important clinical applications.  At UMHS, Dr. Wang will use phage display methods to biopan against purified recombinant protein to identify lead a candidate.  He will optimize the sequence using a structural model, and validate specific binding to the intended target using standard laboratory methods, including siRNA knockdown, competition, and microscopy.  The optimized sequence will be studied in a pre-clinical xenograft model of HCC.  The optimized peptide will be delivered to PKUHSC for validation of specific binding to GPC3 in a pre-clinical model of patient-derived HCC xenografts that provides clinically relevant genetic heterogeneity and GPC3 expression at levels seen in patients.  Validation of specific peptide binding will also be performed using human specimens of HCC ex vivo.

Outcome

• The IRDye800-labeled GPC3 peptide is compatible with the laparoscopic surgical system used by Dr. JY Zhu to perform hepatectomy at PKU. Pre-clinical studies with patient-derived xenografts (PDX) of HCC in a mouse model will be performed at PKU to evaluate binding performance in tissues that provide clinically relevant target expression levels and genetic heterogeneity.

Publications

1. Z.Li, Q. Zhou, J. Zhou, X. Duan, J. Zhu, TD Wang. In vivo fluorescence imaging of hepatocellular carcinoma xenograft using near-infrared labeled epidermal growth factor receptor (EGFR) peptide. BIOMEDICAL OPTICS EXPRESS.2016, 9(7):3163
2. Zhou Q., Li Z, Zhou U, Joshi BP, Li G, Duan X, Kuick R, Owens SR, Wang TD.In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft. Photoacoustics. 2016 Apr 22;4(2):43-54.

Extramural Funding

Ongoing

U01 CA230669 Multi-P.I. AS Lok (contact) 09/01/18 - 08/30/23
NIH/NCI (Consortium on Translational Research in Early Detection of Liver Cancer)
Novel Strategies to Improve Liver Cancer Surveillance Uptake and Early Detection
The goal of this project is to assemble a team of specialists with complementary expertise in liver diseases, liver cancer, radiology, engineering, statistics, and information technology to improve liver cancer surveillance uptake in patients with cirrhosis.

Pending

R01 CA245906 P.I. TD Wang 12/01/19 - 11/30/24
NIH/NCI (U.S.-China Program for Biomedical Collaborative Research)
Precision image-guided detection of hepatocellular carcinoma (HCC)
A multi-modal imaging strategy that combines the physical properties of light and sound will be used to rigorously validate specific uptake of the targeted contrast agent in HCC tumor. Fluorescence provides images over a large field-of-view to visualize systemic biodistribution and tumor localization over time. Photoacoustics provides an assessment of peptide uptake over the tumor depth.

Anna Lok, MD
骆淑芳教授
Alice Lohrman Andrews Research Professor of Hepatology
Assistant Dean for Clinical Research
Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Lai Wei, MD
魏来教授
Vice President, Peking University People's Hospital
Director, Peking University Hepatology Institute

JI Program: GI & Liver

Status: Active/ Ongoing

Summary

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease ranging from steatosis alone to steatohepatitis (NASH) and cirrhosis and is an increasing cause of hepatocellular carcinoma (HCC) worldwide. Global prevalence of NAFLD is increasingly rapidly due to the epidemic of obesity and diabetes. The prevalence of NAFLD among adults is estimated to be 30% in the U.S. and 15% in China. The major causes of NAFLD are obesity, diabetes and insulin resistance; however, NAFLD may be present in lean persons. The finding of NAFLD in lean persons is more common among Asians and Caucasians. This is a prospective observational study with the primary goal to understand the pathogenesis of NAFLD in lean Chinese. This study will employ a novel technique, analytic morphomics, to quantify visceral adipose tissue, ectopic adipose tissue and quality of fat in lean Chinese with NAFLD versus lean Chinese with no NAFLD and obese Chinese with NAFLD. We hypothesize that among lean Chinese, models that include data on the quantity and quality of visceral and ectopic adipose tissue determined by analytic morphomics outperform models that include only routinely available demographics, anthropometrics and laboratory data in predicting risk of NAFLD and to implement interventions to improve outcomes of those who are predicted to have high risk of metabolic abnormalities and progressive liver disease. The study will also support one young investigator from PKUHSC to receive 1-year training in clinical research at Michigan Medicine.

Outcomes

• Enrollment completed at PKU and near completion at UM.
• Trainee mentored by Dr. Anna Lok and Dr. Lai Wei
• Dr. Wei Zhang from PKUHSC completed 14 training at UM as visiting scholar.
• 2 UMMS M1 students completed 6-week summer research program at PKUHSC

Publications

1. Zhang W, Chao S, Chen S, Rao H, Huang R, Wei L, Lok AS. Awareness and knowledge of non-alcoholic fatty liver disease among office employees in Beijing, China. Dig Dis Sci 64: 708-717, 2019. PMID: 30483909.

Extramural Funding

Project indirectly contributed to award of $3.38M U01 from National Cancer Institute, NIH to Dr. Anna Lok, Grace Su (co-I in this study), and Thomas Wang (PI of another JI study).

Jun Li, PhD
李军教授
Professor of Human Genetics
Professor & Associate Chair for Research of Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Yang Ke, MD
柯杨教授
Professor of Oncology
Peking University Health Science Center

JI Program: GI & Liver

Status: Completed

Summary

Esophageal cancers (EC), particularly esophageal squamous cell carcinoma (ESCC), present significant medical and scientific challenges. EC is the sixth most frequent cancer in women, with China accounting for ~50% of EC cases worldwide. Many parts of northern China have some of the highest ESCC incidence levels in the world, yet the genetic and environmental factors underlying such remarkable geographic variation are currently unknown. ESCC is difficult to detect at an early stage, and difficult to treat after diagnosis. Currently, we do not fully understand the major ESCC subtypes in different populations, nor do we understand the patterns of growth, migration, and treatment response among different cells within a tumor. This lack of knowledge impedes effective prevention, accurate diagnosis, personalized treatment, and development of novel drugs. Using a uniquely powerful clinical resource developed at PKUHSC, high-throughput genomic profiling capabilities, and the strong statistical analysis expertise at Michigan Medicine, this collaboration proposed to characterize intratumoral heterogeneity by comparing genomic alterations in different sectors of the same tumor, and contrasting them with surrounding normal tissues as well as the metastatic tumors in nearby lymph nodes. The results will reveal major genes and pathways affected in each patient; an importantly, the regional variation will be analyzed to shed light on the temporal progression of key tumorigenic events, from normal tissue to primary tumor, and to metastasis. Elucidating the somatic mutation sources in ESCC will also help resolve the long-standing controversies regarding the epidemiological factors contributing to ESCC. This study will harness complementary strengths from our two institutions, and is expected to generate new mechanistic insights into within-tumor evolution and genomic diversity of ESCC.

Outcomes

• Two PKUHSC PhD students received extensive training at Michigan Medicine mentored by Dr. Li.
• 146 samples with high-density SNP genotyping and exome sequencing were analyzed and led to numerous publications.

Publications

1. Yuan W, Liu Z, Lei W, Sun L,... Li JZ, Yang K ( June 27, 2017). Mutation landscape and intra-tumor heterogeneity of two MANECs of the esophagus revealed by multi-region sequencing. Oncotarget.
2. Li J, Yan S, Liu Z, … Ke Y. Multiregional sequencing reveal genomic alterations and clonal dynamics in primary malignant melanoma of the esophagus. Cancer Research. 2018;78(2):338-347

Chung Owyang, MD
H Marvin Pollard Professor of Internal Medicine
Chief, Division of Gastroenterology
University of Michigan Medical School
[email protected]

Liping Duan, MD
段丽萍教授
Vice President
Peking University Health Science Center

JI Program: GI & Liver

Status: Completed

Summary

Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder that affects 15-20% of the population in the U.S. The incidence of IBS in China is increasing at an alarming rate. Many challenging issues complicate data interpretation in gut microbiome studies in IBS patients. No single unifying cause has been identified, but recent evidence suggests the involvement of the gut microbiota. Diet has a profound influence on the gut microbial composition and it is unclear whether patients with IBS who eat a vegetarian diet have similar alterations in gut microbial composition as those who consume a meal diet rich in fat and protein. This study investigates the effect of diet and racial factors on the gut microbiota of patients with IBS and aims to fingerprint the microbial composition of a subpopulation of IBS patients who may respond to antibiotic (rifaximin) treatment. The project seeks to determine the differences in gut microbiota between healthy subjects and two groups of patients with IBS consuming either a meat diet or a vegetarian diet. Parallel studies will be conducted in Beijing and Ann Arbor to evaluate the impacts of race and environmental differences on the development of gut dysbiosis in IBS and the clinical response to rifaximin treatment. The study team anticipate only patients showing gut dysbiosis, independent of diet, will respond symptomatically, with normalization of gut mucosal physiology and amelioration of inflammatory tone. This proposal will be the first clinical IBS study with well-phenotyped cohorts to determine the effect of diet and racial factors on gut dysbiosis in IBS. This information is critical for identifying patients who may respond to antibiotic treatment. The key feature of this study of IBS in humans include distinct racial populations and dietary habits. Findings from this seed project will provide unique and novel information to develop hypothesis-driven studies for subsequent extramural funding.

Outcomes

• 119 IBS and 91 healthy controls were enrolled in the study, with 155 completed.
• 1 PKUHSC PhD student received extensive training in microbiome research at Michigan Medicine mentored by Dr. Owyang.
• 58 IBS stool samples and 30 controls stool samples were shipped from PKUHSC to Michigan Medicine for microbiome analyses.
• The results showed a great proportion female patients and meat eaters in the IBS subjects compared to healthy controls. Meat eaters and male gender have a greater predictable relationship related to maximum tolerated rectal sensation.

Anna Lok, MD
骆淑芳教授
Alice Lohrman Andrews Research Professor of Hepatology
Assistant Dean for Clinical Research
Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Lai Wei, MD
魏来教授
Vice President, Peking University People's Hospital
Director, Peking University Hepatology Institute

JI Program: GI & Liver

Status: Completed

Summary

Chronic Hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the U.S. and is emerging to be an important cause of mortality from liver disease in China. While chronic HCV does not always lead to cirrhosis or HCC, it has been estimated that 20% of people with chronic HCV infection progress to cirrhosis. Extensive research on Hepatitis C at both universities has long been established and this collaboration strives to identify genetic markers that predict the progression from chronic HCV infection to cirrhosis and HCC, and to identify and validate blood markers of liver fibrosis and early HCC in patients. The study is being conducted at both Michigan Medicine and PKUHSC hospitals, allowing comparison of genetic and environmental factors from two diverse populations. The data collected from the study will allow for a more in-depth knowledge of chronic HCV and possible treatment options at different stages of the disease.

Outcomes

• Total enrollment includes almost 2,045 patients.
• Awarded $1.4 million U.S. dollars from Collaborative Science Research & Operations, Global Development & Medical Affairs Division of the Bristol-Myers Squibb Company to continue cross-cultural HCV research until 2019.
• Trainees mentored by Dr. Anna Lok and Dr. Lai Wei:
  • 11 UMMS M1 students completed 8-week summer research programs at PKUHSC.
  • 4 UMMS residents completed one-month clinical rotation at PKUHSC.
  • Dr. Ming Yang from PKUHSC received the Fogarty fellowship for an 11-month research virtual training.

Publications

1. Rao HY, Sun DG, Jiang D, …Lok AS, Wei L. (2012) IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis C virus infection. J Viral Hepat. 2012; 19(3): 173-181.
2. Wei L, Lok AS. (2014) Impact of new hepatitis C treatments in different regions of the world. Gastroenterology. 2014; 146(5):1145-50.
3. Wu E, Chen X, Guan Z, …Wei L, Lok AS. (2015) A comparative study of patients’ knowledge about hepatitis C in the United States and in urban and rural China. Hepatol Int. 2015; 9: 58-66.
4. Huiying Rao, Elizabeth Wu, Sherry Fu, Ming Yang, Bo Feng, Andy Lin, Ran Fei, Robert J. Fontana, Anna S. F. Lok, Lai Wei. The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease. Aliment Pharmacol Ther, 2017, 46(8):731-740.
5. Elizabeth Wu, Ming Yang, Huiying Rao, Sherry Fu, Bo Feng, Ran Fei, Andy Lin, Robert J. Fontana, Lai Wei, Anna S. Lok. Temporal changes in the modes of hepatitis C virus transmission in the USA and Northern China. Dig Dis Sci. 2017, 62(8):2141-2149.
6. Neehar D. Parikh, Sherry Fu, Huiying Rao, Ming Yang, Yumeng Li, Corey Powell, Elizabeth Wu, Andy Lin, Baocai Xing, Lai Wei, Anna S. F. Lok. Risk Assessment of Hepatocellular Carcinoma in Patients with Hepatitis C in China and the USA. Dig Dis Sci, 2017, 62(11): 3243-3253
7. Ming Yang, Huiying Rao, Bo Feng, Elizabeth Wu, Lai Wei, Anna S. Lok. Patient Education Improves Patient Knowledge and Acceptance on Antiviral Therapy of Hepatitis C in Rural China. Chin Med J, 2017, 130(22):2750-2751.
8. Ming Yang, Elizabeth Wu, Huiying Rao, Fanny H. Du, Angela Xie, Shanna Cheng, Cassandra Rodd, Andy Lin, Lai Wei, Anna S. Lok. A Comparative Study of Liver Disease Care in the USA and Urban and Rural China. Dig Dis Sci, 2016, 61(10):2847-2856.
9. Jiaxin Huang, Mary L. Guan, Jeremy Balch, Elizabeth Wu, Huiying Rao, Andy Lin, Lai Wei, Anna S. Lok. Survey of hepatitis B knowledge and stigma among chronically infected patients and uninfected persons in Beijing, China. Liver Int, 2016, 36(11):1595-1603.
10. Elizabeth Wu, Tianyi Wang, Tammy Lin, Xisui Chen, Zhe Guan, Claudia Cao, Huiying Rao, Ming Yang, Bo Feng, Sandra Pui, Melvin Chan, Sherry Fu, Andy Lin, Lai Wei, Anna S. Lok. A comparative study of patients' attitudes toward clinical research in the United States and urban and rural China. Clin Transl Sci, 2015, 8(2):123-131.
11. Huiying Rao, Degui Sun, Ruifeng Yang, Feng Liu, Jian Wang, Bo Feng, Nan Wu, Jilian Fang, Guangjun Song, Hui Ma, Fang Guo, Jianghua Wang, Xiaobo Li, Qian Jin, Hong Qin, Hui Zhuang, Lai Wei. The outcome of hepatitis C virus infection in Chinese paid plasma donors: a 12-19-year cohort study. J Gastroenterol Hepatol, 2012, 27(3):526-532.