时间：每周三，14:00 - 15:00

地点：数学高等研究院报告厅

组织者：阮勇斌，黄德力，印焘， 宋海，周家耀

活动安排

3月11日

报告人：吕志民（浙江大学转化医学研究院）

题目：Metabolic Regulation of Cancer and Immunity

摘要：We elucidated instrumental mechanisms of the Warburg effect, discovered the protein kinase and phosphatase activity of metabolic enzymes, and revealed the non-metabolic functions of metabolic enzymes in tumorigenesis. (1) Our work elucidated important mechanisms underlying the RTK-promoted Warburg effect, which are regulated by nuclear function of pyruvate kinase M2 (PKM2) and mitochondrial function of phosphoglycerate kinase 1 (PGK1). (2) We discovered that metabolic enzymes (PKM2, PGK1, PCK1, HK2, PI3K, and fructokinase KHK-A) can function as protein kinases to regulates cell cycle progression, mitochondrial function, autophagy, and de novo nucleic acid synthesis. (3) We discovered for the first time that metabolic enzymes can function as protein phosphatase. Fructose-1,6-bisphosphatase 1 (FBP1) dephosphorylates histone H3 and TERT and suppresses gene transcription. (4) Our work revealed that metabolic enzymes, including fumarase, acetyl-CoA synthetase 2 (ACSS2), and a-ketoglutarate dehydrogenase (KGDH) can possess nonmetabolic functions in regulation of instrumental cellular activities including DNA repair and gene expression. The discoverers of tumor-promoting functions of metabolic enzymes provide novel approaches for diagnosis and treatment of human cancer.

3月18日

报告人：黄德力（浙江大学生命科学研究院）

题目：Multiparatopic antibodies overcome tyrosine kinase inhibitor resistance by inducing lysosomal degradation of EGFR mutants

摘要：Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). To address this issue, we developed a novel therapeutic strategy based on multiparatopic antibodies that induce targeted degradation of EGFR, independent of the driver mutations typically residing in the cytosolic domain. We engineered nanobodies (Nbs) recognizing four distinct epitopes within the EGFR extracellular domain into biparatopic and triparatopic antibody formats. These antibodies effectively promoted EGFR clustering, endocytosis, and lysosomal degradation, resulting in potent suppression of downstream signaling and cell proliferation in NSCLC cell lines carrying diverse EGFR mutations, including those resistant to osimertinib. The degradation process was epitope-dependent and mediated through a dynamin-dependent endocytic pathway. Triparatopic antibodies exhibited superior antitumor efficacy compared to both biparatopic antibodies and osimertinib in xenograft models of TKI-sensitive and TKI-resistant NSCLC cells. Moreover, these antibodies displayed additive effects when combined with osimertinib. We further demonstrated that this degradation mechanism extends beyond EGFR, as antibody-mediated crosslinking similarly triggered PD-L1 degradation. Collectively, this study indicates that multiparatopic antibodies are a potent and mechanistically distinct strategy to overcome TKI resistance by directly degrading the target oncoprotein, with broad applicability to other pathogenic cell surface proteins.

3月25日

报告人：印焘（浙江大学生命科学研究院）

题目：Developing novel strategies to overcome immunosuppression within the tumor microenvironment

摘要：Anti-cancer immunotherapies have demonstrated remarkable success against multiple solid tumors; however, for many patients, efficacy remains modest and temporary due to primary and/or acquired resistance. In recent years, we have sought to identify new mechanisms of immune suppression in the tumor microenvironment. For instance, while investigating novel suppressive mechanisms in melanoma, we discovered that nerve growth factor (NGF) mediates both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor, leading to desensitization of IFN-g signaling, and subsequent exclusion of T and NK cells. In parallel, paracrine NGF suppresses TCR signaling and effector function of T cells. Genetic or pharmacological targeting of NGF sensitizes melanoma to immune checkpoint blockade (ICB) therapy. Together, these findings reveal a comprehensive mechanism by which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thereby providing a novel therapeutic strategy for immunotherapy. 

4月1日

报告人：陈崇（四川大学华西医院）

题目：Epigenetic reprograming, lineage plasticity, and TME remodeling in tumor evolution

摘要：Tumor, as pathologic organs, and tumor cells are highly dynamic during tumor evolution, including tumorigenesis, metastasis, and treatment resistance. Tumor evolution is driven by both tumor cell intrinsic and extrinsic mechanisms. My laboratory is interested in the epigenetic reprogramming and lineage plasticity of tumor cells and remodeling of tumor microenvironment (TME). We have identified multiple epigenetic regulatory genes as novel tumor suppressor genes or oncogenes, revealed new lineage plasticity of resistant tumors. Recently, we found a BBB-like immune-excluding vascular barrier in neuroendocrine tumors, which contributes to their resistance to immunotherapy. I would like to discuss the complexity of tumor cells and tumors as pathologic organs at the molecular and cellular levels, and the hypothesis-driven and data-driven approaches for biomedical research.

4月15日

报告人：刘玉（四川大学华西医院）

题目：The impact of chromosome copy number variations in cancer biology

摘要：Cancer is a genetic disease. In addition to single nucleotide variations (SNVs), chromosomal copy number variations (CNVs), such as deletions or amplifications, are common in many cancers. Tumors harboring CNVs are often associated with drug resistance, relapse, and poor survival. Thus, it is critical to understand the molecular mechanisms underlying chromosomal CNVs. Unlike SNVs, which typically affect a single gene, chromosomal deletions or amplifications involve hundreds of genes simultaneously, posing significant challenges for functional and mechanistic studies. To address this, our group has developed cancer models for several clinically relevant chromosomal deletions, including 17p13 (one of the most frequently deleted regions in cancer), demonstrated their functional roles in cancer biology, and uncovered novel underlying mechanisms.

4月22日

报告人：钱昆（上海交通大学）

题目：Metabolome Engineering

摘要：Metabolome engineering, including profiling and manipulation of small metabolites, is essential in monitoring and control the physiological and pathological process in bio-systems. Metabolic detection is the key in metabolome engineering. Despite that mass spectrometry (MS) enjoys huge application benefits over traditional methods in metabolic detection, present MS approaches, particularly laser desorption/ionization (LDI) MS techniques, urgently need designed materials as efficient matrices and their LDI mechanism is still to be explored, in order to overcome the major limitations in terms of sensitivity, selectivity, throughput, accuracy, and practicability for metabolome engineering. In this talk, we show our recent progress on the design of inorganic particles as novel matrices for LDI MS analysis and their practical application in detection of small metabolites in bio-fluids, for advanced metabolome engineering toward large-scale biomedical use.

4月29日

报告人：魏树梅（浙江大学附属第二医院）

题目：Pathological diagnosis and molecular typing of HBP tumors

摘要：Precise pathological diagnosis and molecular profiling are the key links in achieving individualized treatment of HBP (hepatobiliary and pancreatic) tumors. Tumors exhibit different histological morphologies and microenvironmental backgrounds under the microscope, and this morphological heterogeneity corresponds to different molecular biological characteristics. In recent years, with the update of the 5th edition of the WHO classification of digestive system tumors and the wide application of omics technologies, the classification system of HBP tumors has evolved from relying solely on histomorphology to a comprehensive classification model integrating morphology, immunophenotype, molecular characteristics and clinical information. This presentation focuses on the key points of pathological diagnosis of the HBP tumors and the progress of molecular profiling in this field.

5月6日

报告人：江瑞（清华大学）

题目：TBA

摘要：TBA

5月13日

报告人：曹亚南（上海交通大学）

题目：TBA

摘要：TBA

5月20日

报告人：张世华（中国科学院）

题目：TBA

摘要：TBA

5月27日

报告人：刑栋（北京大学） 

题目：TBA

摘要：TBA

6月3日

报告人：杨灿（香港科技大学）

题目：TBA

摘要：TBA

6月10日

报告人：郑钜圣 （西湖大学）

题目：TBA

摘要：TBA

6月17日

报告人：王哲（ 西京医院）

题目：TBA

摘要：TBA

6月24日

报告人：蔡尚（西湖大学）

题目：TBA

摘要：TBA