MOSAIC: Targeting the Tissue State

MOSAIC：针对组织状态

• 批准号: 10729422
• 负责人: Nhan L Tran
• 金额: $ 34.34万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729422
• 关键词: Acute; Aftercare; Astrocytes; Biological; Biopsy; Bone Marrow; Brain; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Chemoresistance; Conditioned Culture Media; Disease Progression; Endothelial Cells; Extracellular Matrix; Female; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Image; Immune; Immunocompetent; Immunotherapy; In Vitro; Infiltration; Inflammatory; Interleukin-10; Interleukin-6; Ligands; Macrophage; Magnetic Resonance Imaging; Malignant Glioma; Mathematics; Mediating; Mesenchymal; Microglia; Modeling; Molecular; Mutation; Myeloid Cells; Neurons; Non-Malignant; Oligodendroglia; Oncology; Patients; Pattern; Pericytes; Phenotype; Population; Receptor Inhibition; Regimen; Role; Sampling; Signal Pathway; Signal Transduction; Slice; Systems Analysis; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Translations; Tumor Necrosis Factor Receptor; Tumor Promotion; Xenograft Model; anti-PD-L1; cell behavior; cell community; cytokine; effective therapy; imaging facilities; in vivo; insight; male; member; neoplastic cell; novel therapeutic intervention; progenitor; radiological imaging; receptor; receptor expression; recruit; temozolomide; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression

SUMMARY: PROJECT 1: TARGETING GLIOMA TISSUE STATES Glioblastoma (GBM) displays extensive cellular heterogeneity which represents a major obstacle for effective treatment. This cellular heterogeneity not only consists of multiple tumor cell mutation factors that drive distinct tumor cell behavior, but also impacts various non-tumor cells, contributing to tumor initiation, progression, and treatment response. In fact, GBM’s microenvironment is multifaceted and consists of soluble factors, extracellular matrix components, tissue-resident cells (neuron, astrocytes, endothelial cells, pericytes, etc.) and resident (e.g. microglia) or recruited (e.g. bone-marrow derived macrophages) immune cells. Importantly, changes in the cellular composition and cellular phenotypes can alter GBM tissue states to drive tumor growth and therapeutic resistance. Thus, identifying the unique cellular composition and deciphering the multifaceted bidirectional network between tumor cells and tumor microenvironment signals in various GBM tissue states can lead to identification of novel therapeutic strategies. Our preliminary studies using single nucleus RNAseq of pre- and post-treatment GBM has identified 3 tissue states, corresponding to patterns of cohabitation of tumor and non-tumoral cell subpopulations. These correspond to infiltrated brain, highly cellular proliferating tumor, and astrocytic / inflamed reactive tissue, which is observed in the post-treatment samples and enriched in specific populations of myeloid cells and mesenchymal glioma cells. Co-habitation of specific non-tumor cellular phenotypes in the glioma microenvironment may influence glioma states signatures (astrocyte-like/mesenchymal, progenitor, proliferative) that associate with tumor progression and therapeutic response. The goal of this project is to define the patterns of cellular cohabitation associated with the tissue states and the cross-talk signals that influence local tissue state, phenotypic expression, transitions and disease progression. Because of its known role in cross-talk between specific populations in GBM, we will initially test the effects of targeting TWEAK-Fn14 signaling to drive changes in tissue state. We hypothesize that targeting this as well as other key cross-talk signaling pathways will induce tissue state transitions with corresponding alterations in cellular populations that will render tumors more sensitive to therapeutic vulnerabilities and can be leveraged to slow tumor growth/progression. To investigate the potential impact of such key states and their cross-talk, we propose three aims. Aim 1 focuses on refining our understanding of glioma tissue states in both the pre- and post- treatment setting. Aim 2 investigates cross talk between the glioma cells and their microenvironment and how it may influence progression. Aim 3 looks more locally at how cross-talk perturbations may impact tissue state transition.

摘要：项目1：靶向胶质瘤组织状态 胶质母细胞瘤(GBM)表现出广泛的细胞异质性，这是有效治疗的主要障碍。 治疗。这种细胞异质性不仅由多个肿瘤细胞突变因子组成，这些突变因子推动了不同的 肿瘤细胞的行为，但也影响各种非肿瘤细胞，有助于肿瘤的启动、进展和 治疗反应。事实上，GBM的微环境是多方面的，由可溶性因子、胞外因子组成 基质成分、组织驻留细胞(神经元、星形胶质细胞、内皮细胞、周细胞等)和常驻(例如 小胶质细胞)或募集的(如骨髓来源的巨噬细胞)免疫细胞。重要的是， 细胞成分和细胞表型可以改变基底膜组织状态，从而推动肿瘤生长和治疗 抵抗。因此，识别独特的细胞组成并破译多方面的双向 不同GBM组织状态下肿瘤细胞和肿瘤微环境信号之间的网络可导致 确定新的治疗策略。 我们用单核RNAseq对治疗前后的基底膜进行了初步研究，鉴定了3个组织 状态，对应于肿瘤和非肿瘤细胞亚群的共生模式。这些 对应于浸润性脑、高细胞增生性肿瘤和星形细胞/炎症反应组织，它们 在治疗后的样本中观察到，并在特定的髓系细胞和 间充质胶质瘤细胞。特定非肿瘤细胞表型在脑胶质瘤中的共存 微环境可能影响胶质瘤状态信号(星形细胞样/间充质、祖细胞、增殖期) 与肿瘤进展和治疗反应有关。本项目的目标是定义模式 与影响局部组织的组织状态和串扰信号相关联的细胞共生 状态、表型表达、转变和疾病进展。因为它在相声中扮演着已知的角色 在GBM的特定人群之间，我们将初步测试靶向TWEEP-Fn14信号以驱动 组织状态的变化。我们假设，以此为目标以及其他关键的串扰信号通路 会导致组织状态转变，细胞群体发生相应的变化，从而导致肿瘤 对治疗脆弱性更敏感，可用于减缓肿瘤的生长/进展。 为了研究这些关键状态及其串扰的潜在影响，我们提出了三个目标。目标1重点 关于完善我们对治疗前和治疗后的胶质瘤组织状态的理解。目标2 研究胶质瘤细胞与其微环境之间的串扰及其可能影响 进步。AIM 3更多地着眼于串扰如何影响组织状态转换。