Address: Room 143, New Biology Building, Tsinghua University, Haidian District, Beijing.
The 5th Beijing International Symposium on Tumor Microenvironment to be held on September 21st and 22nd, 2019, will last for one and a half days. Experts from relevant fields are invited to give special reports. Speakers include Professor Xinyuan Guan, Professor Yongzhang Luo, Professor Mehdi Mollapour, Professor Yu Sun, Professor Heiichiro Udono, Professor Guowang Xu, Dr. Weiwen Ying and Professor Cheng Yang. Researchers in the relating fields are welcomed to participate in.
Yu SunProfessor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
Cancer is the result of unrestricted cellular expansion after intrinsic and extrinsic countermeasures have failed to prevent carcinogenic events. Complementing apoptosis, cellular senescence represents another ultimate cell-cycle exit program, and operates as a physiological barrier against sporadic but full-blown tumorigenesis. Largely indistinguishable from the terminal replicative arrest that cells usually enter upon progressive erosion of their telomeres, cells may also prematurely undergo senescence in response to acute, severe stresses such as oncogenic activation or genotoxic insults. Specific oncogenes such as RAS or chemotherapeutic agents evoke a typical senescence arrest that exhibits unique morphological and ultrastructural alternations such as enlarged and flattened cell shape, vacuole-enriched cytoplasm with an expanded lysosomal compartment, degradation of the nuclear envelope, and appearance of focal heterochromatin as part of global genomic reorganization. Among multiple changes is the massive synthesis and release of protein species that collectively compose the senescence-associated secretory phenotype (SASP), the full spectrum of which covers pro-inflammatory cytokines, chemokines, growth factors and metalloproteinases.
The SASP can be beneficial or deleterious for physiology, depending on its composition, intensity, and the local microenvironment. Specifically, the SASP is involved in several physiological processes such as promoting tissue repair, fine-tuning the development of embryonic structures and stimulating immune surveillance. However, the deleterious consequences resulting from ineffective clearance of senescent cells and their over-accumulation in tissues can promote various pathologies including cancer. The burden of senescent cells in tissues increases significantly with age, a phenomenon observable in both benign and malignant tumors. Prominently, genetic or chemical ablation of senescent cells in animal models delays the onset of aging-related disorders, prolongs individual lifespan and promotes tissue rejuvenation. Thus, cellular senescence acts as a “double-edged sword” in cancer pathogenesis, which demands further attention in order to support the use of novel senolytics or SASP-modulating compounds for future cancer clinics.
Time: 9:10-10:00, Sept. 21st, 2019
Xinyuan GuanProfessor, Department of Clinical Oncology, the University of Hong Kong.
Cancer associated fibroblasts (CAFs) play critical roles in the establishment of suitable tumor microenvironment. Using FGFR2 as a tracing marker, we systematically studied the process of mobilization, recruitment and maturation of CAFs in esophageal squamous cell carcinoma (ESCC) under the guidance of tumor cells. We found that FGFR2+ fibrocyte progenitors in bone marrow could be mobilized by cancer-secreted FGF2 and recruited into tumor sites via cancer-secreted CXCL12. Moreover, they differentiate into CAFs through the activation of YAP-TEAD complex which is trigger by directly contract with cancer cells. FGF2 and CXCR4 neutralizing antibodies could effectively block the mobilization and recruitment process of FGFR2+ CAFs. These findings give rise to new approaches that target CAFs before their incorporation into tumor stroma.
Time: 10:00-10:50, Sept. 21st, 2019
Yongzhang LuoProfessor, School of Life Science, Tsinghua University
Tumor secreted factors not only provide applications in the identification of novel biomarkers for cancer detection, diagnosis, prognosis and therapeutic monitoring, but also have been gradually recognized as key contributors for cancer progression and drug resistance.
Previously, we found that prior to tumor metastasis, primary tumor can secret factors to prepare a niche for distant metastasis. We reported the regulatory mechanisms of Hsp90α secretion by tumor cells, and the level of extracellular Hsp90α (eHsp90α) is positively correlated with tumor malignancy in cancer patients. Recently, we demonstrated the levels of eHsp90α are determined by ADAM10 expression, which will affect Hsp90α content in exosomes. Clusterin, a protein newly demonstrated to interact with eHsp90α, modulates eHsp90α signaling to promote tumor metastasis. More importantly, blocking eHsp90α and clusterin exhibited decreased metastasis. Collectively, the discovery of a functional correlation between eHsp90α and clusterin also indicates the potential for future development of clusterin and eHsp90α as co-biomarkers for cancer diagnosis and therapeutic targets.
A sensitive and specific diagnosis biomarker, in principle scalable to most cancer types, is needed to reduce the prevalent cancer mortality. Our team have revealed that Hsp90α can be secreted by cancer cells and thus developed a quantitative detection kit for plasma Hsp90α based on ELISA. Based on two clinical trials (enrollment of 2,036 cases and 1,525 cases, respectively), we demonstrated that plasma Hsp90α is a novel biomarker for lung and liver cancer. Recently, another clinical trial with 1,558 enrollments further validated plasma Hsp90α as a pan-cancer biomarker. ROC curve shows that the optimum diagnostic cutoff is 69.19 ng/mL in discriminating various cancer patients from healthy controls (AUC 0.895, sensitivity 81.33% and specificity 81.65% in test cohort; AUC 0.893, sensitivity 81.72% and specificity 81.03% in validation cohort). Similar results are noted in detecting the early stage cancer patients.
Time: 11:10-12:00, Sept. 21st, 2019
Guowang XuProfessor, Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Cancer is not only a complex genetic disease, but also a metabolic disease. Metabolomics is a science to study the whole metabolome in a given biological system under specific conditions. Over last 10 years, metabolomics has become a powerful tool in investigating disease mechanism and discovering metabolic markers.
The core of metabolomics is to discover differential metabolites by comparing the metabolite contents in different groups with multi-/mono-variate analysis. With the improvement of analytical techniques, the focus has shifted from defining differential metabolites toward shedding light on the functions of these important metabolites in a cell, tissue or organism. Such a metabolomics approach promises a better understanding of disease mechanism and identification of potential biomarkers.
In this presentation, we shall report a functional metabolomics platform established in our laboratory including comprehensive nontargeted and pseudotargeted analyses based on one-dimensional/two-dimensional gas or liquid chromatography-mass spectrometry, and cell/molecular biology methods. This platform can be used for not only defining differential metabolites which can be further studied to know the possibility as potential biomarkers, but also unraveling the mechanistic association between metabolites and specific biological events. The newest results will be given to show the applications of developed methods in studying the metabolic reprogramming of hepatocellular carcinoma (HCC) and prostate cancer, explaining the functions of ‘oncometabolites’, and defining risk biomarkers for the early detection of liver cancer.
Time: 14:30-15:20, Sept. 21st, 2019
Heiichiro UdonoProfessor, Department of Immunology, Okayama University Graduate School of Medicine
Metformin (Met) is the most widely used drug in the world as a first choice for treatment of patients with type 2 diabetes (T2DM). Intriguingly, Met is known to reduce the rates of cancer incidence and mortality of patients with T2DM, comparing with those taking other drugs. Using mice tumor models, we previously demonstrated the anti-tumor effect of Met is mediated by CD8+ tumor infiltrating T lymphocytes (TILs), as the effects was canceled in T cell deficient mice and in WT mice depleted of CD8+T cells in vivo. Met confers synergistic effect with anti-PD-1 Ab, thus, better tumor inhibitory effect than either mono-therapy alone, through induction of vigorous proliferation of CD8TILs that can secrete multiple cytokines. The action of Met on CD8TILs seems to be mediated by reactive oxygen species (ROS), since in vivo elimination of ROS by N-acetyl Cysteine (NAC) or GSH, completely abrogates the effect. Met-induced mitochondrial ROS elevates glycolysis in CD8TILs, whereas downregulates that of tumor cells. This indicates that Met improves metabolic imbalance between CD8TILs and tumor cells, until otherwise tumor cells dominate immune cells by taking large amount of glucose.
The above mentioned metabolic change is also appreciated in regulatory T cells (Treg) and CD11b+ cells including myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs). With Met administration, metabolic change from oxidative phosphorylation (OxPhos) to glycolysis is evident in TAMs, which skews phenotypic change of TAMs from M2-to M1-like macrophages, resulting in growth inhibition of certain tumors even in T cell deficient mice. We will discuss how Met affects metabolic states in immune cells by which apparent inhibition of tumor growth is achieved in vivo.
Time: 15:20-16:10, Sept. 21st, 2019
Dinggang LiChief surgeon & professor, Beijing Ludaopei Hematological Hospital
At present, conventional surgery, radiotherapy and chemotherapy have been difficult to effectively treat patients with advanced cancer.
To this end, we explored an innovative idea of multidisciplinary comprehensive clinical treatment.
Through multi-detection techniques of gene detection, immune detection, combined with routine blood biochemical detection, cytopathological detection, nuclear magnetic resonance and CT examination, the life data of internal environment changes of patients with advanced cancer were fully and personally obtained.
At the same time, through accurately evaluate the patient's life performance status and body endurance to future treatment, the personalized multi-disciplinary comprehensive treatment program for patients were designed and developed .
Through the combined application of operation, radiotherapy and chemotherapy, gene therapy, immunotherapy, hyperthermia, argon-helium cryosurgery, minimally invasive ablation and no-invasive high intensity focused ultrasound(HIFU) knife, all life values of the patient's internal environment were effectively stabilized and protected, and the synchronous effect of precise treatment and effective rehabilitation were obtained, and satisfactory clinical results were achieved. All eight cases of advanced cancers we treated were summarized for discussion and sharing
Time: 16:30-17:20, Sept. 21st, 2019
Mehdi MollapourProfessor, Department of Urology, Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University
The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that modulates its chaperone cycle and affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Our data shows that loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitors. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to Hsp90 inhibitors, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.
Time: 9:10-10:00, Sept. 22nd, 2019
Weiwen YingCEO, Ranok Therapeutics Co., Ltd.
HSP90 has been exploited as a molecular target to treat patients with various human diseases. Instead of the traditional tactic to simply inhibiting HSP90, other ways to use HSP90 to help delivering better therapeutics have emerged in the recent years. One approach is to conjugate a small-molecule toxin to an HSP90 binder. As a result, the toxin can be selectively retained in tumorous tissues due to the overrepresentation of activated HSP90 and subsequently released to render the antitumor efficacy. Such approach can provide an expanded therapeutic window and thus better outcome for many anticancer drugs; another approach is to explore the chaperone complex as a protein-degrading machinery and apply this mechanism to purposely remove certain oncogenic protein. In this presentation we will discuss these technological advancements and their application in pharmaceutical research and development.
Time: 10:00-10:50, Sept. 22nd, 2019
Cheng YangProfessor, Dean of College of Pharmacy, Nankai University
Epithelial–mesenchymal transition (EMT) is an important mechanism of metastasis and malignant progression of hepatocellular carcinoma (HCC). However, the transcriptional regulation mechanism of EMT in clinic remains poorly understood. Some transcriptional co-activators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive the robust expression of genes. In this study, we demonstrate that Twist1 and YY1, which are important transcription factors of EMT, interact with histone acetyltransferase p300 and form phase-separated nucleation spots in HCC cells. The phase-separated Twist1–YY1 droplets can form local high-concentration interaction hubs at super-enhancers of miRNA-9 and activate its expression, thus further inducing EMT and promoting the malignant evolution of HCC. EMT can be inhibited when such phase separation of Twist–YY1 condensates was disrupted by metformin. This study preliminarily elucidates that the transcriptional factor complex involved in EMT can form phase-separated condensates near super-enhancers to promote the expression of oncogenes in HCC cells, which provides a potential target for the therapy of HCC and offers insights into the mechanism by which metformin inhibits HCC.
Time: 11:10-12:00, Sept. 22nd, 2019