Weiping Zou, MD. PhD
Professor of Surgery
Michigan Medicine

Chao Zhong, PhD
Professor, Institute of System Biomedicine School of Basic Medical Sciences
Peking University Health Science Center

JI Program: Cancer and Precision Health

Project Status: Active/Ongoing

Lymph nodes are involved in antigen presentation, T cell priming and activation, which are essential for initiating anti-tumor immunity. However, sentinel LNs (or tumor draining LNs) are one of the most common sites of tumor metastasis. The immunological significance of tumor metastatic LNs in the tumor immune responses remains elusive. Furthermore, it remains an open question whether surgical removal of metastatic LNs is an effective approach. The overall goal of this proposal is to understand, and potentially resolve this immunological and clinical paradox. It has been reported that tumor tertiary lymphoid structures (TLSs) are associated with enhanced responses to cancer immunotherapy, indicating that TLSs are involved in promoting the restoration of adaptive antitumor immune responses. Furthermore, lymph node metastases are prognostically important. However, it is poorly defined if tumor lymph node metastasis, compared to other organ site metastasis, alters therapeutic responses in the immune checkpoint inhibitor (ICI). Our published data suggests that specific organ site metastases, such as liver metastasis, affects T cell responses and antitumor immunity in preclinical models and in patients with cancer. Accordingly, we hypothesize that the contribution of lymph node metastases to immune tone and immunotherapy efficacy is critical. Thus, in this research project we will perform clinical studies to further determine the impact of lymph node metastasis on immune tone and ICI responses in patients with cancer, including breast cancer, melanoma, and colorectal cancer in the first 2-year study. Animal models of lymph node metastases will be developed to address the exact impact of lymph node metastases on CD8+ T cells in responses to immunotherapy. Furthermore, the molecular mechanisms and innate/adaptive immune subsets involved in this process will be elucidated, and the immune responses in TDLNs will be assessed and compared to that in TLSs in tumors. Therefore, this research project will shed new light on the contribution of lymph node metastasis to immune tone and immunotherapy efficacy and will have implications for optimizing therapeutic strategies for patients with lymph node metastasis.

Joshi Alumkal, PhD
Professor of Internal Medicine
Michigan Medicine

Hongquan Zhang, PhD
Professor and Director, Peking University Cancer Precision Medicine Program
Peking University Health Science Center

JI Program: Cancer and Precision Health

Project Status: Active/Ongoing

Lineage plasticity (LP) is a biological process that promotes cellular adaptation to stress and can result in change in cellular state or identity. LP occurs on a continuum, ranging from epithelial to mesenchymal transition (EMT) to a more dramatic shift in differentiation program. Importantly, LP is increasingly recognized as a particularly virulent mechanism of treatment resistance in cancer through our work and others’. LP occurs de novo or under the pressure of therapies—particularly those that block factors that are critical for promoting a default lineage program of a cell. The prostate and breast are both hormonally-responsive tissues, and nuclear hormones receptors—the androgen receptor (AR) in prostate cells and the estrogen receptor (ER) in breast cells—are critical for proliferation and differentiation of these tissues. Because of this, hormonal therapies that block the AR or ER are the principal treatment for each disease. In prostate cancer, the incidence of LP has increased in recent years due to widespread use of novel, potent AR signaling inhibitors (ARSIs). Further, transition of tumors after ER inhibitor treatment from ER-positive to ER-negative is also commonly seen . Based on these observations, we postulate that there are commonalities in the molecular mechanisms that underlie LP in prostate and breast cancers. There are no effective therapies for patients whose tumors have undergone LP. Thus, there is a clear need to improve our understanding of key tumor-intrinsic and microenvironmental mediators of LP so that new treatment approaches can be developed.

Jiaqi Shi, MD, PhD
Associate Professor of Pathology
Michigan Medicine

Yinmo Yang, MD
Professor of Hepatobiliary and Pancreatic Surgery
Director, Center for Translational Cancer Research of Peking University First Hospital
Director, Peking University First Hospital
Peking University Health Science Center

JI Program: Cancer and Precision Medicine

Project Status: Active/Ongoing

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with an overall 5-year survival rate of 11%. One of the main reasons for the dismal prognosis of PDAC is early liver metastasis. However, the molecular mechanism of early liver metastasis from PDAC remains elusive. In previous studies, we found that hypoxic PDAC-derived exosomal miRNAs could promote hepatic stellate cell (HSC) activation. HSCs are known components of the prometastatic liver microenvironment [1]. We have used combined single-cell RNA sequencing (scRNA-seq) and multiplex immunohistochemistry (mIHC) technologies to reveal tumor microenvironment heterogeneity of PDAC [2,3]. We have also established a liver metastasis PDAC animal model and collected PDAC clinical specimens and follow-ups. The overall goal of this project is to integrate the resources of both UM and PKU to jointly explore the molecular mechanism of liver metastasis from PDAC and establish the predicted model of early liver metastasis. We plan to further clarify the mechanism of PDAC-derived exosomal miRNAs activating HSCs and remodeling the tumor immune microenvironment (TIME) of liver metastasis. Combined scRNA-seq and mIHC will be used to explore the differences in TIME between the primary tumor and matched liver metastasis and the role of activated HSCs in reprogramming the TIME of liver metastasis. In addition, we will establish and validate the predicted model of early liver metastasis based on the exosomal miRNAs profile of the peripheral blood and portal vein plasma. This project will help elucidate the mechanism of liver metastasis from PDAC, provide new ideas for diagnosing and treating PDAC, and promote deep collaborations between U-M and PKU.

Qing Li, MD, PhD
Associate Professor of Cell & Developmental Biology
Associate Professor of Internal Medicine
[email protected]

Yujun Dong, MD
董玉君教授
Professor of Hematology
PKU First Hospital

JI Program: Cancer & Precision Medicine

Project Status: Active/Ongoing

Despite the recent development of novel drugs and therapeutic strategies, Multiple myeloma (MM) remains an incurable disease, and most patients relapse even after allogeneic hematopoietic stem cell transplantations (allo-HSCT). Available data showed that immune check-point inhibitors are not as effective in MM as in Hodgkin Lymphoma, and immune evasion of myeloma cells against cellular immunity may be an important factor to explain this refractoriness. However, the mechanism of immune evasion in myeloma cells has not been elucidated. ER associated degradation (ERAD) complexes are important protein quality control systems to ensure the proper processing, folding and assembly of plasma membrane proteins including cell surface

antigens and antigen presentation complexes. Our preliminary data showed that the key molecule in Hrd1 ERAD, Sel1L, was expressed in myeloma cell lines and primary MM samples. Furthermore, the cell surface level of peptide-HLA complex (pHLA) on human MM cell lines was significantly altered after Sel1L knockdown. Thus, we hypothesize that Sel1L/Hrd1ERAD may be involved in antigen processing and presentation in myeloma cells, and modulating ERAD might be a new strategy to overcome the immune evasion of MM. The proposed studies will allow us to develop productive collaborations to identify mechanisms of immune evasion in MM, and develop new strategies to enhance response of myeloma cells to immunotherapies.

Max Wicha, MD
Madeline and Sidney Forbes Professor of Oncology
Director, Forbes Institute for Cancer Discovery
Professor of Internal Medicine
[email protected]

Ming Luo, PhD
Associate Research Scientist
Department of Internal Medicine

Wei Wei, MD
韦伟教授
Professor and Director
Breast and Thyroid Surgery
Peking University Shenzhen Hospital

JI Program: Cancer & Precision Health

Project Status: Active/Ongoing

Intratumor heterogeneity, which favors the selection of drug-resistant tumor cells with cancer stem cell (CSC) properties, constitutes one of the greatest challenges in cancer treatment. Two prevailing models of chemo-resistance arise in tumor cells: the enrichment of pre-existing CSCs and stress-induced dedifferentiation of differentiated bulk cancer cells (DCCs) into CSC-like phenotypes. However, to what extent and how DCC dedifferentiation occurs in response to therapeutic stress remain largely elusive. Exosomes are extracellular vesicles of 50-140 nm in size containing proteins, RNA/DNA, lipids, and metabolites, which mediate juxtracrine/paracrine signaling to promote cancer cell plasticity and metastatic progression. We hypothesize that, exosome communications between CSCs and DCCs are augmented by chemotherapy-induced stress, promoting the dedifferentiation of DCCs into chemo-resistant CSCs. Specific Aims of  this pilot grant include: 1) Using CSC epithelial (E) and mesenchymal (M) fluorescent reporters established in different breast cancer cell lines to assess the extent of dedifferentiation from DCCs when treated with or without chemotherapeutics, and determine if exosome secretion from CSCs is enhanced by chemotherapy to promote DCC dedifferentiation;  2) Using zebrafish embryo and mouse xenograft models, we will examine if CSC E/M reporter expression and tumorigenic/metastatic capacity of DCCs are induced when pre-treated with exosomes derived from various CSC states; 3) We will investigate if chemotherapy-induced exosome secretion from breast cancer patient CSCs facilitates the dedifferentiation of DCCs, and define the molecular mechanisms of exosome communications between CSCs and DCCs elicited by therapeutic stress. These studies will result in the development of innovative imaging technologies and animal models to trace tumor cell dedifferentiation at single-cell resolution and provide mechanistic insights to overcome chemo-resistance in advanced breast cancer with the potential to improve patient outcome.

Christine Ye, MD
Assistant Professor of Internal Medicine

Xiao-Jun Huang, MD
黄晓军教授
Director of Hematology
Peking University People's Hospital

JI Program: Cancer & Precision Medicine

Project status: Active/Ongoing

Multiple myeloma (MM) is the second most common hematologic malignancy. Recent years of rapid advancement in therapeutic landscape have resulted in deeper remission and longer survival in MM patients. However, many patients still relapse throughout different stages of disease course. This project seeks to investigate the role of comprehensive immune profiling in myeloma microenvironment by applying cutting edge technology CyTOF with a panel of extensive immune markers to identify the immune cell subsets, including cytotoxic and suppressive immune cells. This project is aimed to associate immune signatures with clinical outcomes including deep clinical response such as minimal residual disease (MRD) remission in MM patients at different time points of treatment course and establish a potential immune signature model, including difference between Chinese and American patients. The immune cells distribution and their spatial relationship with myeloma cells in MM bone marrow tumor microenvironment will also be explored using Imaging Mass Cytometry. It is predicted that distinctive immune patterns in bone marrow tumor microenvironment as well as in peripheral blood may help to decipher the biological mechanisms of immune reconstitution in MM patients who responded well to treatments and achieved more favorable clinical outcome including MRD remission.

Andrea Tosisco, MD
Professor of Internal Medicine
University of Michigan Medical School
[email protected]

John Kao, MD
Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Wen-Qing Li, PhD
李文庆教授
Professor of Cancer Epidemiology
Peking University Cancer Hospital & Institute
[email protected]

JI Program: Cancer/Precision Health

Active/Ongoing

Gastric cancer (GC) is a major public health concern worldwide.  Chronic inflammation is an important causative factor for the development of gastric neoplasia. One hypothesis is that inflammation and mucosal injury alter the normal homeostatic mechanisms of the gastric epithelium leading to the development of metaplasia, dysplasia and, ultimately, to neoplasia.  Both Spasmolytic Peptide Expressing Metaplasia (SPEM), which is characterized by the aberrant expression of Trefoil Factor 2 (TFF2) and of mucins that bind the lectin GSII at the base of glands of the oxyntic mucosa, and Intestinal metaplasia (IM), have been recognized as precursor lesions for GC. However, it appears that only some, but not all patients with metaplasia develop GC.  Thus, it is conceivable that there could be specific genetic signatures and environmental factors responsible for the expression of different pathological phenotypes.  The mechanisms leading to metaplasia and to its progression to neoplasia have been poorly characterized.  The bone morphogenetic proteins, (BMPs) have been shown to inhibit gastric inflammation, cell proliferation and the growth of gastric neoplasms.  We previously reported that inhibition of BMP signaling in the stomach of mice enhances Helicobacterinduced inflammation, stimulates epithelial cell proliferation and causes metaplasia and dysplasia, suggesting that alterations in BMP signaling might lead to pathological state of the gastric mucosa in humans. In this application, using proteomics, metabolomics, transcriptomics, and genomics we will characterize subjects with metaplastic changes of the gastric mucosa that progress to dysplasia and GC, placing particular emphasis on the expression of BMP-mediated pathways.  In order to explore in more details the mechanisms underlying these events, we will use mouse models to define the role of inhibition of BMP signaling and inflammation in the development of metaplasia and dysplasia.  These studies will provide new insight into the factors that control the metaplasia progression cascade, improving our ability to achieve early detection and treatment of gastric dysplasia and neoplasia.

Arul Chinnaiyan, MD, PhD
Professor of Pathology, Urology
Director, Michigan Center for Translational Pathology
University of Michigan Medical School
[email protected]

Yuxin Yin, MD, PhD
尹玉新教授
Professor of Pathology
Dean of Pathology
Director, PKU Institute of Systems Biomedicine
Peking University Health Science Center
[email protected]

JI Program: Cancer/Precision Health

Status: Active/Ongoing

As cancer researchers, new technologies present us with exciting opportunities to address challenges in the field on a global scale. For instance, most cancer diagnostics do not undergo comprehensive testing in diverse patient populations, even though genomic studies have found important molecular differences in cancers between ethnicities. For cancer biomarker development, several validation centers exist in individual countries, but global validation centers are lacking. To address this need, we propose to form the Michigan-Peking Cancer Biomarker Collaborative with the objective of developing novel cancer biomarkers across patient populations in China and the United States, the first- and third-most populated countries in the world. We will begin the Collaborative with development of biomarker assays for detection and risk stratification of prostate cancer. Current prostate cancer screening methods, such as prostate-specific antigen (PSA) testing, have several pitfalls that limit their utility, with one of the most pressing issues being that they are not able to identify potentially aggressive disease to guide appropriate treatment. In collaboration with academic and industry partners, our group at Michigan Medicine previously developed the Michigan Prostate Score (MiPS) test that combines urinary transcript levels of TMPRSS2-ERG and the long non-coding RNA (lncRNA) PCA3 with serum levels of PSA to detect clinically significant prostate cancer, providing a more accurate assessment than PSA alone. However, the transcripts included in our current MiPS assay are not specific to aggressive disease. In the time since MiPS was established, we have performed several studies that have led to a vast compendium of novel prostate cancer-associated transcripts, including thousands of lncRNAs and circular RNAs (circRNAs). For the studies in this application, we will leverage these discoveries to generate a novel expanded quantitative PCR-based MiPS assay (MiPS-QPCR) and a next-generation sequencing-based MiPS assay (MiPS-NGS) that can detect high grade prostate cancer non-invasively with urine samples. Development of MiPS-QCPR will allow rapid clinical transition from our existing MiPS test, while establishment of the MiPS-NGS platform will provide more levels of biomarker information (genetic, transcriptional, and epigenetic). We will also leverage the expertise of our team at Peking University Health Science Center (PKUHSC) in machine learning and metabolomics approaches to develop a complementary lipidomics biomarker assay for detection of aggressive prostate cancer with plasma or urine samples. Critically, all assays will be validated and fine-tuned for accuracy in patient populations from both institutions. The aims of the Collaborative are ambitious but will lead to impactful results for cancer patients in both countries, and it is our goal to become a model global biomarker validation center to fill a current void in this vital arena.

Duxin Sun, PhD
JG Searle Endowed Professor of Pharmaceutical Sciences
Professor in Pharmaceutical Sciences
University of Michigan
[email protected]

Ning Zhang, PhD
张宁教授
Vice President
Peking University Health Science Center

Program: Cancer and Precision Health

Status: Active/ Ongoing

The advent of extensive genomic and epigenetic studies have shown that different cancer cell subpopulations are present in any given patient, each with its own unique response to therapies. Therefore, targeted therapy that only inhibits one subpopulation of cancer cells without eliminating other non-responsive sub-populations are bound to lead to relapse even though patients may show early clinical remission. Focusing on breast and liver cancers, we plan to use novel single-cell analysis and molecular beacon to identify tumor heterogeneity in order to inform patient-specific treatment plans. At the end of this project, we expect to have a positive impact by changing the paradigm for cancer classification and treatment and potentially provide new strategy to attempt to “cure” advanced breast or liver cancer. Specifically, (1) classification of advanced breast cancers or liver cancers with multiple lesions should no longer be based on subtypes or one molecular target, but rather based on the intra-tumoral heterogeneity of each tumor, which requires very different treatment options; (2) the inter-tumoral heterogeneity of primary and metastatic tumors (or multiple lesions) requires different drug combinations; and (3) the inter-tumoral heterogeneity from each individual patient also requires individualized combination of drug therapy. We envision that once we have established the database for this information, it will be feasible to rapidly translate to clinical trials where individualized combinations of therapies can be tailored to eliminate each sub-population of cancer cell heterogeneity and potentially “cure” cancer in the patients with breast or liver cancer.