Deconstruct tumor microenvironment in medulloblastoma

解构髓母细胞瘤的肿瘤微环境

基本信息

批准号：
9152584
负责人：
Hui Zong
金额：
$ 37.63万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/9152584
关键词：
Address Adverse effects Applications Grants Astrocytes Brain Brain Neoplasms Cells Child Childhood Malignant Brain Tumor Coculture Techniques Critical Pathways Cultured Tumor Cells Cytoplasmic Granules Data Desmoplastic Development Effectiveness Environment Genetic Genetic Models Growth Human IGF1R gene Immunology In Situ Hybridization Individual Innovative Therapy Insulin-Like Growth Factor I Interleukin 4 Receptor Interleukin-4 Label Lead Life Malignant Neoplasms Malignant neoplasm of brain Methods Microglia Modeling Mus Mutation Neurons Normal tissue morphology Organ Pathway interactions Patients Principal Investigator Problem Sets Process Production 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-Derived Ursidae Family Work astrocyte-derived tumor base cancer therapy cell growth cell type chemotherapy clinical application combinatorial conventional therapy cytokine genomic aberrations immunoregulation improved inhibitor/antagonist killings macrophage medulloblastoma mouse model mutant neoplastic cell nervous system disorder novel research study response smoothened signaling pathway treatment strategy tumor tumor initiation tumor microenvironment tumor progression tumorigenic

项目摘要

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.

肿瘤是活器官。有效的癌症治疗不仅必须处理遗传改变在肿瘤细胞中，以及支持性肿瘤微环境（TME）。我们的实验室研究 TME在髓母细胞瘤（最常见的恶性小儿脑肿瘤）中的作用。虽然改善的放射线和化学疗法大大提高了患者的生存率，传统治疗通常会导致幼儿造成毁灭性的副作用。自从异常的声音刺猬（SHH）以来颗粒神经元前体（GNP）中的信号传导是脱瘤的常见原因髓母细胞瘤，可以有效杀死肿瘤细胞的SHH途径的抑制剂已是发达。但是，抗这些抑制剂的患者的毒性和突变大大降低他们的临床适用性。为了确定可以减轻该问题的其他机制，我们着手研究与小鼠遗传模型和发现星形胶质细胞和肿瘤相关的小胶质细胞/巨噬细胞的显着存在（tams）。我们还用QRT-PCR筛选了一系列生长因子，发现IGF1适合比尔作为TME因子，因为肿瘤质量始终升高，但肿瘤不存在 GNP。进一步的研究表明，IGF1极大地促进了在培养中肿瘤GNP的增殖，并且在GNP中特别丢失IGF1R导致肿瘤进展停止。使用原位杂交，我们将TAM定位为tAM，而不是其他细胞类型作为分泌TME TME细胞类型。肿瘤细胞与TAM的共同培养导致持续增殖，这种作用由 IGF1阻滞剂。最后，我们发现IL-4是由TME中的星形胶质细胞产生的，已知可以促进小胶质细胞/巨噬细胞中的IGF1表达。总之，我们已经确定一个以IGF1信号传导为中心的TME网络，以促进髓母细胞瘤的进展。基于在我们的初步发现中，我们假设这破坏了沿着TME-tumor的串扰 IGF1轴应是髓母细胞瘤的有效治疗策略。在这笔赠款中应用，我们建议通过直接抑制肿瘤细胞中的IGF1R信号传导来检验我们的假设，通过从TAM中删除IGF1，并通过从星形胶质细胞到TAM切断IL-4信号传导减少其IGF1产生。我们已经组建了一个鼠标遗传学专家团队，免疫学和人脑肿瘤病理学，并有信心我们的研究会做出贡献发展高效，新颖的治疗策略。从长远来看，原则从我们的研究中出现的不仅应受益于髓母细胞瘤患者，而且还应提供其他神经疾病的创新疗法的基础。