Deconstruct tumor microenvironment in medulloblastoma

肿瘤是一个有生命的器官。有效的癌症治疗必须不仅处理基因改变 在肿瘤细胞内，也包括支持肿瘤微环境(TME)。我们的实验室研究了 TME在儿童最常见的恶性脑肿瘤--髓母细胞瘤中的作用虽然 改进的放射和化疗极大地提高了患者的存活率，传统疗法 往往会给幼儿带来毁灭性的副作用。自从反常的音速刺猬(嘘) 颗粒神经元前体(GNPs)中的信号是促结缔组织增生症的常见原因 髓母细胞瘤是Shh途径的抑制剂，可以有效地杀死肿瘤细胞 发展起来的。然而，患者的毒性和抵抗这些抑制物的突变大大降低。 它们的临床适用性。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 (TAMS)。我们还用qRT-PCR筛选了一组生长因子，发现IGF1符合 比尔是一种TME因子，因为它在肿瘤中持续升高，但在肿瘤中不存在 GNP。进一步研究表明，IGF1在培养中极大地促进了肿瘤GNPs的增殖， 而IGF1R在GNPs中的特异性缺失导致肿瘤进展受阻。在现场使用 通过杂交，我们确定TAMS而不是其他细胞类型为分泌IGF1的TME细胞类型。 肿瘤细胞与TAMs共培养导致持续增殖，这一效应被 IGF1-封闭剂。最后，我们发现IL-4是由TME中的星形胶质细胞产生的，这是 已知可促进小胶质细胞/巨噬细胞表达IGF1。总而言之，我们已经确定 以IGF1信号为中心的TME网络促进髓母细胞瘤的进展。基座 根据我们的初步发现，我们假设破坏TME与肿瘤的串扰 IGF1轴有望成为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信号来检验我们的假设， 通过从TAMs中去除IGF1，并切断星形胶质细胞到TAMs的IL-4信号，从而 减少他们的IGF1产量。我们已经组建了一支老鼠遗传学专家团队， 免疫学和人脑肿瘤病理学，并相信我们的研究将有助于 以开发高效、新颖的治疗策略。从长远来看，这些原则 从我们的研究中发现的不仅应该造福于髓母细胞瘤患者，而且还可以提供 为其他神经疾病的创新疗法奠定了基础。

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.