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: 10705775
• 负责人: JOAN MASSAGUE
• 金额: $ 49.56万
• 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/10705775
• 关键词: Adenocarcinoma Cell; Alzheimer' s Disease; Apoptosis; Astrocytes; Basement membrane; Binding; Blood Vessels; Brain; Breast Cancer Cell; Cancer Patient; Cell Communication; Cells; Clinical; Communication; Complex; Disease associated microglia; Disseminated Malignant Neoplasm; ERBB2 gene; Exclusion; 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; 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; Patients; Phenotype; Physicians; Primary Neoplasm; Research; Research Personnel; Resistance; Sampling; Shapes; Signal Transduction; System; Systems Analysis; Systems Biology; Testing; Therapeutic Intervention; Tissues; Transcriptional Regulation; autocrine; brain cell; brain shape; cancer cell; cell type; cerebral capillary; contextual factors; differential expression; knowledge of results; lung colonization; malignant breast neoplasm; mortality; mouse model; multiple omics; pharmacologic; 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therapeutic development; therapeutic evaluation; triple-negative invasive breast carcinoma; tumor; tumor growth; unpublished works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

项目一脑转移瘤肿瘤-间质相互作用的系统分析 实验负责人：Massagué 计算主管：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小鼠模型和临床 这些样本旨在揭示转移性癌细胞在大脑中定植的策略。脑转移是一种 乳腺癌和肺癌患者发病率和死亡率的主要原因。马萨盖实验室开创了 以确定脑转移和相关细胞间相互作用的介质，并使这一问题 系统级的分析我们最近发现三阴性脑转移灶 乳腺癌（TNBC）、HER 2+乳腺癌（HER 2BC）和肺腺癌（LUAD） 并且患者样品在癌细胞和宿主之间的空间关系上显示出显著差异 组织. TNBC和LUAD细胞通过L1 CAM沿沿着脑毛细血管扩散，形成血管周围集落网络 与小胶质细胞和星形胶质细胞混合。与之形成鲜明对比的是，HER 2BC细胞通过形成 不包括脑实质细胞的致密球形集落。高表达特异性细胞外 基质蛋白通过HER 2BC细胞驱动这种球状生长。值得注意的是，血管周围和球状集落 触发先前在阿尔茨海默氏症中定义的不同疾病相关小胶质细胞（DAM）先天免疫阶段 疾病目的1是阐明DAM在转移相关小胶质细胞中的调控机制。我们 将通过分析脑转移中稳态到DAM转变的转录调控， 转移相关小胶质细胞的单细胞多组学特征。我们将剖析癌细胞如何触发， 通过检验HER 2BC凋亡触发2期DAM的假设来调节DAM应答，而 TNBC的增强的存活保留了1期DAM。我们将确定TNBC内在抗性的驱动因素， 通过计算引导搜索TNBC细胞中的自分泌促存活信号传导来检测细胞凋亡。我们将确定 1期DAM如何支持肿瘤生长。我们将试图将转移相关的小胶质细胞与激活的 小胶质细胞状态跨上下文的监督基因集分析。目标2：定义时空 进展和多细胞通讯在脑转移瘤的系统水平的分析。我们和 其他人已经显示除了小胶质细胞之外的多种细胞类型参与支持脑转移。这些 相互作用要求对多细胞通信的各种集合进行全面的询问， 形成脑转移瘤。我们将利用我们的LUAD到脑转移模型来研究“什么”细胞类型， 程序构成了多细胞的通信合奏。我们将分析完整的转移集落， 细胞定位于“何处”以及哪些程序差异表达。我们将揭开细胞 通过计算推断多细胞集合体的形成和影响， 从转移菌落的快照中。我们将扰动推断的集合以测试治疗干预 范例由此产生的知识，丰富了CSBC研究中心免疫学家的投入， 医生，将最终指导治疗干预的发展，以靶向脑转移瘤。 1