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therapeutic development; therapeutic evaluation; triple-negative invasive breast carcinoma; tumor; tumor growth; unpublished works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I.脑转移中肿瘤-间质相互作用的系统分析 实验主演：马萨圭 计算领头羊：佩尔 项目总结 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 样本来解开转移性癌细胞用来侵占大脑的策略。脑转移瘤是一种 乳腺癌和肺癌患者发病和死亡的主要原因。马萨古实验室开创了研究先河 确定脑转移的介质和相关的细胞-细胞相互作用，并将这一问题置于 佩尔实验室的系统级分析。我们最近发现，脑转移灶的三阴性 小鼠乳腺癌(TNBC)、HER2+乳腺癌(HER2BC)和肺腺癌(LUAD)模型 患者样本在癌细胞和宿主之间的空间关系上表现出显著的差异 组织。TNBC和LUAD细胞通过L1CAM沿脑毛细血管扩散，形成血管周围集落网络 它们与小胶质细胞和星形胶质细胞混合在一起。与之形成鲜明对比的是，HER2BC细胞通过形成 不包括脑实质细胞的致密球状集落。特异性胞外蛋白的高表达 HER2BC细胞的基质蛋白驱动这种球状生长。值得注意的是，血管周围和球状集落 触发阿尔茨海默病患者不同的疾病相关小胶质细胞(DAM)先天免疫阶段 疾病。目的1阐明肿瘤转移相关小胶质细胞中DAM的调控机制。我们 将通过分析来解决脑转移瘤从稳态到DAM转变的转录调控 转移相关小胶质细胞的单细胞多组学图谱。我们将剖析癌细胞是如何触发和 通过测试HER2BC细胞凋亡触发阶段2 DAM的假设来调节DAM反应，而 提高了TNBC的存活率，保留了1期大坝。我们将确定TNBC-内在抗药性的驱动因素 通过计算机引导在TNBC细胞中寻找自分泌促进生存信号的细胞凋亡。我们将决定 第一阶段DAM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的 通过有监督的基因集分析，小胶质细胞在不同环境中的状态。目标2是定义时空 用系统水平分析脑转移瘤的进展和多细胞通讯。我们和 其他研究表明，除小胶质细胞外，多种类型的细胞参与支持脑转移。这些 相互作用需要对多细胞通信的各种组合进行全面的询问， 塑造脑转移瘤。我们将利用我们的LUAD到脑转移模型来研究什么细胞类型和 程序构成了多蜂窝通信合奏。我们将分析完整的转移克隆以了解 “在哪里”细胞是局部化的，哪些程序是差异表达的。我们将“如何”解开这些细胞 程序通过计算推断多细胞系的形成和影响来塑造转移 从转移菌落的快照中。我们将扰乱推断的集合以测试治疗干预 范例。由此产生的知识，在CSBC研究中心免疫学家和 最终将指导针对脑转移瘤的治疗干预措施的发展。 1