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

基本信息

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
项目类别：
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&apos 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therapeutic development therapeutic evaluation triple-negative invasive breast carcinoma tumor tumor growth unpublished works

项目摘要

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-基质相互作用的系统分析实验负责人：Massagué 计算主管：Pe’er 项目概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样本来揭示转移性癌细胞在大脑中定植的策略。 Massagué 实验室开创了乳腺癌和肺癌患者发病和死亡的主要原因。确定脑转移的介质和相关细胞间相互作用，并将这个问题解决我们最近与 Pe’er Lab 进行了系统级分析，发现三阴性脑转移灶。小鼠模型中的乳腺癌 (TNBC)、HER2+ 乳腺癌 (HER2BC) 和肺腺癌 (LUAD) 和患者样本在癌细胞和宿主之间的空间关系上表现出显着差异 TNBC 和 LUAD 细胞通过 L1CAM 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的 HER2BC 细胞通过形成在大脑中定居。排除脑实质细胞的紧凑的球状集落，高表达特定的细胞外细胞。 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。触发先前在阿尔茨海默病中定义的独特的疾病相关小胶质细胞 (DAM) 先天免疫阶段目标 1 是阐明转移相关小胶质细胞中的 DAM 调节机制。将通过分析脑转移中稳态到 DAM 转变的转录调控我们将剖析癌细胞如何触发和转移的单细胞多组学特征。通过测试 HER2BC 细胞凋亡触发第 2 阶段 DAM 的假设来调节 DAM 反应，而提高 TNBC 的存活率并保留第一阶段 DAM 我们将确定 TNBC 内在耐药性的驱动因素。我们将通过计算引导搜索 TNBC 细胞中的自分泌促生存信号来确定细胞凋亡。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细胞联系起来。通过监督基因集分析来确定小胶质细胞的跨环境状态。目标 2 是定义时空。我们通过系统级分析来研究脑转移中的多细胞通讯。其他研究表明，除小胶质细胞外，多种细胞类型也参与支持脑转移。相互作用需要对多细胞通讯的各种整体进行全面的研究我们将利用我们的 LUAD 到脑转移模型来研究“什么”细胞类型和我们将分析完整的转移集落来学习。细胞定位在“哪里”以及哪些程序有差异表达，我们将揭示细胞“如何”表达。和程序通过计算推断多细胞群体的形成和影响来塑造转移我们将扰乱推断的集合来测试治疗干预。由此产生的知识，通过 CSBC 研究中心免疫学家的投入而得到丰富。医生将最终指导针对脑转移的治疗干预措施的开发。 1