Project I: Systems analysis of tumor-stroma interactions in brain metastasis

项目一：脑转移中肿瘤-基质相互作用的系统分析

• 批准号: 10525192
• 负责人: JOAN MASSAGUE
• 金额: $ 53.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525192
• 关键词: Adenocarcinoma Cell; Alzheimer' s Disease; Apoptosis; Astrocytes; Basement membrane; Binding; Brain; Breast Cancer Cell; Cancer Patient; Cell Communication; Cells; Clinical; Communication; Complex; Disease associated microglia; Disseminated Malignant Neoplasm; ERBB2 gene; Extracellular Matrix Proteins; Factor Analysis; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Homeostasis; Immune; Immune system; Immunologist; Label; Laminin; Lead; Learning; Logic; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Metastatic malignant neoplasm to brain; Microglia; Modeling; Morbidity - disease rate; Natural Immunity; Nature; Neoplasm Metastasis; Neural Cell Adhesion Molecule L1; PF4 Gene; Patients; Pharmacology; Phenotype; Physicians; Primary Neoplasm; Research; Research Personnel; Resistance; Sampling; Shapes; Signal Transduction; Supervision; System; Systems Analysis; Systems Biology; Testing; Therapeutic Intervention; Tissues; Transcriptional Regulation; autocrine; brain cell; brain shape; cancer cell; cell type; cerebral capillary; differential expression; knowledge of results; lung colonization; malignant breast neoplasm; mortality; mouse model; multiple omics; prevent; programs; response; single cell analysis; single-cell RNA sequencing; spatial relationship; spatiotemporal; therapeutic development; therapeutic evaluation; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; unpublished works

Project I. Systems Analysis of Tumor-Stroma Interactions in Brain Metastasis Experimental Lead: Massagué Computational Lead: Pe’er PROJECT SUMMARY The overall goal of this project is to apply systems-level computational approaches to mouse models and clinical samples to unravel strategies that metastatic cancer cells employ to colonize the brain. Brain metastasis is a major cause of morbidity and mortality in breast and lung cancer patients. The Massagué Lab pioneered studies to identify mediators of brain metastasis and relevant cell-cell interactions, and are subjecting this problem to systems-level analysis with the Pe’er Lab. We recently found that brain metastatic lesions of triple-negative breast cancer (TNBC), HER2+ breast cancer (HER2BC), and lung adenocarcinoma (LUAD) in mouse models and patient samples display remarkable differences in the spatial relationship between cancer cells and the host tissue. TNBC and LUAD cells spread along brain capillaries via L1CAM, forming perivascular colony networks that intermingle with microglia and astrocytes. In sharp contrast, HER2BC cells colonize the brain by forming compact spheroidal colonies that exclude brain parenchymal cells. High expression of specific extracellular matrix proteins by HER2BC cells drives this spheroidal growth. Notably, the perivascular and spheroidal colonies trigger distinct disease-associated microglia (DAM) innate immunity stages previously defined in Alzheimer’s disease. Aim 1 is to elucidate the DAM regulatory mechanisms in metastasis-associated microglia. We will resolve transcriptional regulation of the homeostasis-to-DAM transition in brain metastasis by analyzing single-cell multiomic profiles of metastasis-associated microglia. We will dissect how cancer cells trigger and modulate DAM responses by testing the hypothesis that HER2BC apoptosis triggers stage 2 DAM, whereas enhanced survival of TNBC retains stage 1 DAM. We will identify drivers of TNBC-intrinsic resistance to apoptosis by computationally guided search for autocrine pro-survival signaling in TNBC cells. We will determine how stage 1 DAM supports tumor growth. We will seek to connect metastasis-associated microglia to activated microglia states across contexts by supervised gene set analysis. Aim 2 is to define spatiotemporal progression and multicellular communication in brain metastasis by a systems-level analysis. We and others have shown the engagement of multiple cell types besides microglia to support brain metastasis. These interactions call for a comprehensive interrogation of the various ensembles of multicellular communication that shape brain metastasis. We will leverage our LUAD-to-brain metastasis models to study “what” cell types and programs constitute multicellular communication ensembles. We will analyze intact metastatic colonies to learn “where” the cells are localized and which programs are differentially expressed. We will unravel “how” the cells and programs shape metastasis by computationally inferring the formation and impact of multicellular ensembles from snapshots of metastatic colonies. We will perturb the inferred ensembles to test therapeutic intervention paradigms. The resulting knowledge, enriched with the input of the CSBC Research Center immunologists and physicians, will ultimately guide the development of therapeutic interventions to target brain metastases. 1

项目I.脑转移中肿瘤 - 细胞瘤相互作用的系统分析 实验铅：马萨吉 计算铅：pe'er 项目摘要 该项目的总体目标是将系统级计算方法应用于鼠标模型和临床 样品揭示了转移性癌细胞的策略，使大脑定居。脑转移是 乳腺癌和肺癌患者发病率和死亡率的主要原因。 Massagué实验室开创性研究 确定脑转移的介体和相关的细胞 - 细胞相互作用，并将此问题置于 使用PE'ER实验室的系统级分析。我们最近发现三阴性的脑转移性病变 小鼠模型中的乳腺癌（TNBC），HER2+乳腺癌（HER2BC）和肺腺癌（LUAD） 患者样品在癌细胞与宿主之间的空间关系上显示出显着差异 组织。 TNBC和LUAD细胞通过L1CAM沿着脑毛细血管扩散，形成血管周菌落网络 与小胶质细胞和星形胶质细胞相结合。形成鲜明的对比，HER2BC细胞通过形成大脑定居 紧凑的球体菌落排除了脑实质细胞。特定细胞外的高表达 HER2BC细胞的基质蛋白驱动该球体生长。值得注意的是，血管周围和球形菌落 触发与先前在阿尔茨海默氏症中定义的不同的疾病相关的小胶质细胞（DAM）先天免疫学阶段 疾病。目的1是阐明与转移相关的小胶质细胞中的大坝调节机制。我们 通过分析，将解决脑转移中体内稳态到达元过渡的转录调节 转移相关小胶质细胞的单细胞多素谱。我们将剖析癌细胞的触发方式和 通过测试HER2BC凋亡触发2阶段大坝的假设来调节大坝的反应，而 TNBC的生存增强保留了1阶段的大坝。我们将确定TNBC intrinsic抗性的驱动因素 通过计算指导搜索TNBC细胞中的自分泌促生存信号传导的细胞凋亡。我们将确定 第1阶段水坝如何支持肿瘤生长。我们将寻求将转移相关的小胶质细胞与激活联系起来 小胶质细胞通过监督基因集分析在环境中循环。目标2是定义时空 通过系统级分析，脑转移中的进展和多细胞通信。我们和 其他人则表明，除了小胶质细胞以外，多种细胞类型的参与以支持脑转移。这些 互动要求对多细胞沟通的各种集合进行全面审问 塑造脑转移。我们将利用我们的luad到脑转移模型来研究“什么”细胞类型和 程序构成多细胞通信合奏。我们将分析完整的转移菌落以学习 “位置”单元格位于本地化，并且表达了哪些程序。我们将揭开“细胞”的“如何” 程序和程序通过计算上推断多细胞合奏的形成和影响来塑造转移 来自转移菌落的快照。我们将扰动推断的合奏来测试治疗干预 范式。由CSBC研究中心免疫学家和 医师最终将指导理论干预措施以靶向脑转移的发展。 1