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：以表观智能体解读单细胞表观基因组语言

摘要：尽管单细胞染色质开放性测序使得绘制单个细胞内的表观基因组景观成为可能，但测序数据的复杂性和下游任务的多样性仍对开发精密且多功能的计算方法提出了迫切需求。针对这一问题，我们最近研发了首个单细胞表观基因组基础模型——EpiAgent。该模型通过创新设计的细胞语言模型将130万调控元件无损压缩编码为最长8192个词元的“细胞语句” ，利用双向注意力机制捕捉调控网络蕴含的细胞异质性，进而基于最大规模单细胞染色质开放性数据库Human-scATAC-Corpus在5百万细胞上完成预训练。大量综合测试表明，EpiAgent在细胞表征、细胞类型注释、数据填补等典型下游任务中表现卓越，大幅超越现有方法。更为重要的是，语言模型赋予了EpiAgent灵活的扩展能力。通过引入代表样本批次的词元，EpiAgent能够实现参考数据整合与查询数据映射，从而支撑细胞图谱构建与利用。通过引入代表细胞扰动的词元，EpiAgent能够有效预测外部刺激和遗传扰动下的细胞响应，从而支撑个性化精准用药。通过对细胞语句的修改，EpiAgent能够进行调控元件的虚拟敲除实验，从而支撑药物靶点发现。

5月13日

报告人：郑钜圣 （西湖大学）

题目：人体肠道微生物多模态组学与代谢稳态调控

5月20日

报告人：张世华（中国科学院）

题目：空间生物学的智能解码、集成与生成

摘要：空间转录组学的技术进步对于更好地理解生物研究中组织的结构和功能至关重要。人工智能算法与空间转录组学的结合为破译组织结构提供了有效途径。我们团队开发了STA-系列空间转录组学AI工具,比如STAGATE和STAligner。最近，我们提出了空间多组学整合工具STAMO、定向或时变基因检测工具STAVAG，空间转录组学的高保真模拟和全视图3D建模工具STADiffuser，跨物种空间转录组集成工具STACAME，以及空间组学可扩展通用解析工具STAX。在这次报告中，我将以其中的典型算法和工具为例，介绍如何利用深度学习有效地建模空间转录组学数据，并用以解决生物学中的关键问题。

5月27日

报告人：邢栋（北京大学） 

题目：单细胞分辨率下真核基因组的结构与功能

摘要：细胞间的多样性不仅体现在转录组层面，也体现在包括核小体占据、染色质状态和基因组空间结构在内的多层表观遗传差异上。为系统理解这些调控维度如何共同塑造细胞身份，我们开发了单细胞四组学测序方法 CHARM，实现了在同一细胞中对基因组三维构象、组蛋白修饰、染色质可及性和基因表达的并行测量。该方法为在单细胞分辨率下整合解析三维表观基因组提供了新工具，也为揭示复杂组织中不同细胞类型的调控图谱奠定了基础。

6月3日

报告人：杨灿（香港科技大学）

题目：Characterizing Tissue Microenvironments by Deciphering Shared and Condition-Specific Multicellular Programs in Multi-Slice Spatial Transcriptomics

摘要：Cellular functions within the tissue ecosystem are profoundly shaped by their immediate local environments, known as functional niches. Deciphering the functional niches within complex tissues is essential to understanding how localized cellular interactions drive overall tissue physiology and pathology. While spatial transcriptomics enables high-resolution mapping of gene expression in situ, systematically deciphering cell–cell signaling dialogues remains a significant challenge. Specifically, characterizing a functional niche requires not only defining the spatial communities formed by co-localized cell neighborhoods, but also deciphering the active molecular dialogues and ligand-receptor signaling driving these interactions. Here, we introduce S2-MAP, a statistical model designed to infer putative interacting neighbor cells and the resulting alterations in gene expression programs at the same time. Tailored for multi-condition and multi-slice ST data, S2-MAP enables the detection of both shared and condition-specific interaction niches. In a pancreatic cancer data, our framework traced niche remodeling during tumor progression and captured condition-specific cellular interaction shifts driven by p53 deficiency. Furthermore, across mouse kidney datasets spanning six stages of injury and repair, we identified injury-specific fibro-inflammatory niches and reconstructed the complete trajectory of cellular crosstalk.

6月9日

报告人：曹亚南（上海交通大学）

题目：从ChinaMAP到单细胞扰动组：复杂疾病的细胞应激机制与靶点发现

摘要：大规模人群组学研究为我们理解复杂疾病的遗传架构提供了重要数据与关联信息。跨越从数据发现到机制解析与靶点转化，是当前计算生物学与精准医学的重要领域。以解析2型糖尿病细胞应激机制的研究为案例，探索应用可扩展的单细胞扰动技术，对复杂疾病的潜在关键基因进行高通量功能筛选。在此基础上，探索从群体组学数据驱动发现到单细胞扰动精准解析，为复杂疾病和肿瘤的药物靶点机制和药物发现拓展跨学科的研究策略。

6月17日

报告人：王哲（ 西京医院）

题目：淋巴瘤的时空病理研究-DLBCL/SLL的实践

摘要：淋巴瘤是淋巴造血系统恶性肿瘤，其免疫微环境对于肿瘤生物学行为非常重要，仍有许多类型淋巴瘤的肿瘤微环境的成分、作用尚未阐明。我们利用时空病理的方法对弥漫性大 B 细胞淋巴瘤（DLBCL）和慢性淋巴细胞白血病 / 小淋巴细胞淋巴瘤（CLL/SLL）进行细致研究，发现免疫微环境的特点，影响微环境的重要因素、形成机制和临床意义，进一步深入了解肿瘤发展过程中的重要分子标志物，将这些分子标志物用于诊断、预后预测或治疗靶点。为淋巴瘤的治疗策略提供新的思路。

6月24日

报告人：蔡尚（西湖大学）

题目：The Mystery of Intratumor Bacteria in Breast Cancer Malignancy

摘要：菌群微环境在肿瘤发生发展中的功能研究进展表明，肠道菌群、肿瘤内菌群在调控肿瘤的生长、进展和治疗反应方面发挥着重要作用。这些微生物通过影响免疫反应、代谢活性和肿瘤细胞信号传导等机制，参与了肿瘤的恶性转化、侵袭和转移过程。近期，我们通过建立改进的组织菌群定量方法，深入分析了乳腺癌肿瘤菌群的结构与动态变化，结合小鼠模型功能性实验，我们发现乳腺癌存在低丰度的肿瘤菌群，肿瘤内细菌，尤其是定位在细胞质内的胞内菌，对乳腺癌转移以及复发灶的免疫微环境建立具有关键调控作用。肿瘤菌群的干预能够有效抑制乳腺癌的转移以及复发。这些研究有望为深入理解和干预肿瘤微生态系统提供新的思路和方法。

7月1日

报告人：李子青（西湖大学）

题目：AI+生命科学：从生物分子到虚拟细胞

摘要：Advances in AI-empowered protein research, such as AlphaFold2, have significantly impacted molecular biology over the past five years and brought about profound transformation to life science research. Looking ahead to the next 5 to 10 years and beyond, this talk presents the continuing momentum, focusing on key problems and challenges in AI for cell biology, AI Virtual Cell (AIVC) in particular.I will share the latest progress in cell state modeling, causal gene regulation network and cell perturbation.

7月7日

报告人：曾凡新（达州市中心医院）

题目：基于人工智能技术的临床转化研究体系构建

摘要：数字医疗与人工智能的技术迭代革新，已成为现代临床医学转型升级的核心驱动力。传统诊疗体系长期存在医疗数据碎片化、影像阅片人力成本高、病灶早期筛查效能不足、基础研究临床转化周期冗长等突出瓶颈。本团队以人工智能技术为抓手深耕各类临床场景，围绕电子病历文本智能解析、多模态医学影像自动判读、多维组学数据整合挖掘三大主线开展系统性研发，构建数字孪生人，实现病历结构化分析、个体化辅助诊断及大规模人群疾病筛查。依托标准化临床数据库破除技术落地壁垒，全面提升临床诊疗质量与运行效率，缩短医学科研成果转化周期，创新智能医学研究范式。

7月22日

报告人：陈广勇（中国科学院杭州医学研究所）

题目：TBA

摘要：TBA

7月29日

报告人：金若凡（北京中关村学院）

题目：TBA

摘要：TBA