Cancer-associated fibroblasts and extracellular matrix remodeling in pediatric neuroblastoma

小儿神经母细胞瘤中癌症相关成纤维细胞和细胞外基质重塑

• 批准号: 10701757
• 负责人: Nicolas Peterson
• 金额: $ 4.37万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701757
• 关键词: ADAMTS; ADAMTS1 gene; Actins; Adrenal Glands; Adrenal Neuroblastoma; Adult; Affect; Attention; Automobile Driving; CD4 Positive T Lymphocytes; Cancer Biology; Cells; Cephalic; Cessation of life; Chemicals; Child; Childhood; Childhood Solid Neoplasm; Chromium; Chromosome Mapping; Collagen; Confocal Microscopy; Cytokine Gene; Data; Deposition; Development; Disease; Dissociation; Enterobacteria phage P1 Cre recombinase; Enzymes; Etiology; Evolution; Extracellular Matrix; Fibroblasts; Flow Cytometry; Gene Deletion; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Heterogeneity; Immune; Immune signaling; Immune system; Immunocompetent; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunologics; Incidence; Inflammation; Investigation; Laboratories; Laboratory Study; Laminin; Learning; Location; MYCN gene; Macrophage; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Molecular; Monitor; Mus; Myeloid Cells; Neoplasm Metastasis; Neuroblastoma; Neuroendocrine Cell; Patients; Phenotype; Process; Progressive Disease; Proteins; Proteoglycan; Proteolysis; Rag1 Mouse; Resected; Role; Signal Transduction; Site; Smooth Muscle; Solid; Solid Neoplasm; Statistical Data Interpretation; Stromal Cells; Survival Rate; T-Lymphocyte; Testing; Tissue-Specific Gene Expression; Tumor Promotion; Tumor Volume; WT1 gene; angiogenesis; anti-tumor immune response; cancer cell; cell type; chemokine; crosslink; cytokine; experimental study; high risk; immune cell infiltrate; improved; in vivo; inducible Cre; insight; lymphocyte trafficking; patient subsets; premalignant; prevent; recruit; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic; versican

PROJECT SUMMARY Extracellular matrix (ECM) remodeling is a critical process within the solid tumor microenvironment. Cancer- associated fibroblasts (CAFs) are the primary producers of matrix proteins and remodeling enzymes that cross- link and degrade matrix proteins. CAFs are enigmatic in that they can promote or impede tumor growth, suggesting heterogeneity that is not completely understood. How CAF heterogeneity evolves over tumor progression and how this evolution impacts ECM remodeling within solid tumors remain an outstanding question in cancer biology. Recent studies have focused on CAF function in models of adult cancer, but little attention has been directed toward understanding CAF heterogeneity and ECM remodeling in childhood cancers, which are etiologically different diseases. Neuroblastoma (NB) is a childhood cancer of neuroendocrine cells that accounts for 15% of pediatric cancer deaths. The 5-year overall survival rate for high-risk NB remains at 50%, highlighting the need for a deeper understanding of the molecular and immunological mechanisms driving tumorigenesis in this subset of patients. Like other solid tumors, the NB tumor microenvironment includes malignant cells, CAFs, and immune cells. Our laboratory studies NB using a penetrant, spontaneous model of high-risk NB (TH-MYCN, AlkF1178L/+) in immunocompetent mice, allowing in vivo investigation of the tumor immune microenvironment from tumorigenesis to progressive disease. Using this model, we previously demonstrated the pro-tumorigenic role of macrophages and CD4+ T cells by showing that their depletion significantly reduced the formation of tumors and extended survival. My preliminary experiments utilizing 10X Chromium gene expression analysis of stromal cells from nascent and mature tumors identified two distinct subsets of CAFs characterized by alpha smooth muscle actin (Acta2) and Wilms tumor 1 (Wt1) expression. Interestingly, only Wt1 CAFs expressed chemokines and cytokines involved in recruitment of myeloid and T cells. Wt1 CAFs were enriched in the early tumor microenvironment and expressed genes encoding ADAMTS enzymes involved in degradation of the proteoglycan versican. Our preliminary findings indicate that Wt1 CAFs may be a crucial early recruiter of pro-tumorigenic immune cells in our model of neuroblastoma. The studies proposed will assess how CAF heterogeneity affects ECM remodeling over neuroblastoma progression, examine tumor-CAF and CAF-immune signaling, and test the effect of perturbing ECM deposition and degradation on tumor formation and progression. Together, these studies will generate new and exciting information about the tumor microenvironment and potential vulnerabilities to exploit in pediatric solid tumors.

项目摘要 细胞外基质（ECM）重塑是实体瘤微环境中的关键过程。癌症- 相关的成纤维细胞（CAF）是基质蛋白和重塑酶的主要生产者， 连接并降解基质蛋白。CAF是神秘的，因为它们可以促进或阻碍肿瘤生长， 这表明了尚未完全理解的异质性。CAF异质性如何在肿瘤中演变 进展以及这种演变如何影响实体瘤中的ECM重塑仍然是一个悬而未决的问题 在癌症生物学中。最近的研究主要集中在成人肿瘤模型中CAF的功能，但很少有人关注 已被导向理解CAF异质性和ECM重塑在儿童癌症， 是不同的病因。 神经母细胞瘤（NB）是一种神经内分泌细胞的儿童癌症，占儿童癌症的15% 死亡高风险NB的5年总生存率仍为50%，这突出表明需要更深入的研究。 理解在这部分患者中驱动肿瘤发生的分子和免疫学机制。 与其他实体瘤一样，NB肿瘤微环境包括恶性细胞、CAF和免疫细胞。我们 实验室研究NB使用渗透剂，自发模型的高风险NB（TH-MYCN，AlkF 1178 L/+）， 免疫活性小鼠，允许在体内研究肿瘤免疫微环境， 从肿瘤发生到疾病进展。使用该模型，我们先前证明了 巨噬细胞和CD 4 + T细胞的减少显著减少了肿瘤的形成， 延长生存期。 我的初步实验利用10倍铬基因表达分析的基质细胞从新生和 成熟肿瘤鉴定出两种不同的CAF亚群，其特征在于α平滑肌肌动蛋白（Acta 2）和 Wilms肿瘤1（Wt 1）表达。有趣的是，只有Wt 1型CAFs表达参与细胞增殖的趋化因子和细胞因子。 骨髓和T细胞的募集。Wt 1 CAFs在早期肿瘤微环境中富集并表达 编码ADAMTS酶的基因参与蛋白聚糖多功能蛋白聚糖的降解。我们的初步 研究结果表明，在我们的模型中，Wt 1 CAFs可能是促肿瘤免疫细胞的关键早期招募者。 神经母细胞瘤这项研究将评估CAF异质性如何影响ECM重塑， 神经母细胞瘤进展，检查肿瘤CAF和CAF免疫信号传导，并测试干扰的影响， ECM沉积和降解对肿瘤形成和发展的影响。这些研究将产生新的 以及有关肿瘤微环境和儿科潜在漏洞的令人兴奋的信息 实体瘤