Deconstruct tumor microenvironment in medulloblastoma

解构髓母细胞瘤的肿瘤微环境

• 批准号: 9284536
• 负责人: Hui Zong
• 金额: $ 42.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284536
• 关键词: Address; Adverse effects; Alpha Granule; Applications Grants; Astrocytes; Astrocytoma; Brain; Brain Neoplasms; Cells; Child; Childhood Malignant Brain Tumor; Coculture Techniques; Critical Pathways; Cytoplasmic Granules; Data; Desmoplastic; Development; Effectiveness; Environment; Genetic; Genetic Models; Growth Factor; Human; IGF1R gene; Immunology; In Situ Hybridization; Individual; Innovative Therapy; Insulin-Like Growth Factor I; Interleukin 4 Receptor; Interleukin-4; Label; Lead; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Microglia; Modeling; Mosaicism; Mus; Mutation; Neurons; Normal tissue morphology; Organ; Pathway interactions; Patients; Principal Investigator; Problem Sets; Production; Quantitative Reverse Transcriptase PCR; Radiation; Resolution; Role; Route; SHH gene; Sampling; Signal Transduction; Sonic Hedgehog Pathway; Specimen; Survival Rate; System; Testing; Therapeutic; Toxic effect; Transgenes; Treatment Efficacy; Tumor Pathology; Tumor-Associated Process; Tumor-Derived; Tumorigenicity; Ursidae Family; Work; astrocyte-derived tumor; base; cancer therapy; cell growth; cell type; chemotherapy; clinical application; combinatorial; conventional therapy; cytokine; experimental study; genomic aberrations; immunoregulation; improved; inhibitor/antagonist; killings; macrophage; medulloblastoma; mouse model; mutant; neoplastic cell; nervous system disorder; novel; response; smoothened signaling pathway; treatment strategy; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenic

Tumor is a living organ. Effective cancer treatment must deal with not only the genetic alterations within tumor cells, but also the supportive tumor microenvironment (TME). Our lab studies the roles of TME in medulloblastoma, the most common malignant pediatric brain tumor. Although improved radiation and chemotherapy greatly boosted patient survival rates, traditional treatment often leads to devastating side effects in young children. Since aberrant sonic hedgehog (Shh) signaling in granule neuron precursors (GNPs) is a common cause of desmoplastic medulloblastoma, inhibitors of the Shh pathway that can effectively kill tumor cells have been developed. However, toxicity in patients and mutations that resist these inhibitors greatly reduced their clinical applicability. To identify additional mechanisms that could alleviate that problem, we set out to investigate mechanisms of tumor-TME interactions with mouse genetic models and found the prominent presence of astrocytes and tumor-associated microglia/macrophages (TAMs). We also screened a panel of growth factors with qRT-PCR, and found that IGF1 fits the bill as a TME factor since it is consistently elevated in the tumor mass, but is absent from tumor GNPs. Further studies showed that IGF1 greatly promoted proliferation of tumor GNPs in culture, and that the loss of IGF1R specifically in GNPs led to halted tumor progression. Using in situ hybridization, we pinpointed TAMs but not other cell types as the IGF1-secreting TME cell type. Co-culture of tumor cells with TAMs led to sustained proliferation, an effect abrogated by the IGF1-blocking agent. Finally, we found that IL-4 is produced by astrocytes in the TME, which is known to promote IGF1 expression in microglia/macrophages. In conclusion, we have identified a TME network that centered on IGF1 signaling to promote medulloblastoma progression. Based on our preliminary findings, we hypothesize that disrupting the TME-tumor crosstalk along the IGF1 axis should be an effective therapeutic strategy for medulloblastoma. In this grant application, we propose to test our hypothesis by directly inhibiting IGF1R signaling in tumor cells, by removing IGF1 from TAMs, and by cutting off the IL-4 signaling from astrocytes to TAMs thus reduce their IGF1 production. We have assembled a team of experts in mouse genetics, immunology, and human brain tumor pathology, and are confident that our studies will contribute to the development of highly effective, novel treatment strategies. In the long term, the principles that emerge from our studies should not only benefit medulloblastoma patients, but also provide a basis for innovative therapies for other neurological diseases.

肿瘤是一个活的器官。有效的癌症治疗不仅要处理基因改变， 在肿瘤细胞内，而且还支持肿瘤微环境（TME）。我们的实验室研究 TME在髓母细胞瘤中的作用，髓母细胞瘤是最常见的儿童恶性脑肿瘤。虽然 改进的放疗和化疗大大提高了患者的生存率， 往往会对幼儿产生毁灭性的副作用。自从变异音刺猬（嘘） 颗粒神经元前体（GNP）中的信号传导是促结缔组织增生的常见原因。 髓母细胞瘤，Shh通路的抑制剂，可以有效地杀死肿瘤细胞， 开发然而，患者的毒性和抵抗这些抑制剂的突变大大减少 其临床适用性。为了确定可以缓解这一问题的其他机制，我们 着手研究肿瘤-TME与小鼠遗传模型相互作用的机制， 发现星形胶质细胞和肿瘤相关的小胶质细胞/巨噬细胞的显著存在 （TAM）。我们还用qRT-PCR筛选了一组生长因子，发现IGF 1符合 bill作为TME因子，因为它在肿瘤块中持续升高，但在肿瘤中不存在 GNP。进一步的研究表明，IGF 1极大地促进了培养的肿瘤GNP的增殖， 并且GNP中特异性IGF 1 R的缺失导致肿瘤进展停止。使用原位 通过杂交，我们确定TAM而不是其他细胞类型为分泌IGF 1的TME细胞类型。 肿瘤细胞与TAM的共培养导致持续的增殖，这一效应被TAM所消除。 IGF 1阻断剂。最后，我们发现IL-4是由TME中的星形胶质细胞产生的， 已知促进小胶质细胞/巨噬细胞中的IGF 1表达。最后，我们确定了 一个以IGF 1信号为中心的TME网络，以促进髓母细胞瘤进展。基于 根据我们的初步发现，我们假设破坏TME-肿瘤串扰沿着 IGF 1轴可能是髓母细胞瘤有效的治疗策略。在这份赠款中， 应用，我们提出通过直接抑制肿瘤细胞中的IGF 1 R信号传导来测试我们的假设， 通过从TAM中去除IGF 1，并通过切断从星形胶质细胞到TAM的IL-4信号传导， 减少IGF 1的产生。我们召集了一个老鼠遗传学专家小组， 免疫学和人类脑肿瘤病理学，并相信我们的研究将有助于 发展出高效新颖的治疗策略。从长远来看，原则 我们的研究不仅对髓母细胞瘤患者有益， 为其他神经系统疾病的创新疗法奠定了基础。