Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors

随着原发性或全身性癌症部位治疗结果的改善，脑转移的临床重要性 (BM)在增长所有癌症患者中有24%至45%发生BM，大多数来自肺，乳腺或 黑色素瘤原发性癌症，但很少有BM患者寿命超过一年，BM占20%， 每年癌症死亡人数具有讽刺意味的是，最近化疗的进展进一步增加了 BM，因为大多数治疗剂不能有效地穿透血脑屏障（BBB）和肿瘤 细胞会把大脑当成避难所因此，加深对 促进BM增长的机制，可以专门利用这些机制来克服当前的限制， 疗法 与多种癌症共有的涉及癌细胞-宿主相互作用的分子机制相反， 导致器官特异性转移的类型，一组高度不同的结构，解剖，生理和 分子因子调节向脑的转移。星形胶质细胞是最常见的神经胶质细胞，约占 所有人类脑细胞，是BM的一个很好的表征的病灶周围成分，最近的发现，包括 我们的研究提供了令人信服的证据，表明星形胶质细胞和癌细胞之间的分子串扰是不可或缺的， BM开发。虽然开创性的发现表明与星形胶质细胞的相互作用发生在早期和晚期， 在肿瘤定植过程的晚期，我们对星形胶质细胞-癌细胞相互作用的理解是 有限公司在初步研究中，我们使用了我们的细胞间通讯探测器（CCCExplorer）， 独特的计算建模工具，用于鉴定新型PCDH 7-EGFR、IL 6-IL 6 R和CCL 5-CCR 5 星形胶质细胞-肿瘤串扰信号在调节BM中的作用。根据这些观察，并鉴于分泌 神经胶质细胞的性质，我们建议在这里测试的假设，串扰与星形胶质细胞来源的分泌 因子对于肿瘤细胞在脑中的定植是至关重要的。 假设一个更复杂的旁分泌信号网络可以在不同的时间动态进化， BM发展的各个阶段，并且相互作用可以为癌症提供抗和促转移刺激 细胞，我们将通过以下目的来测试我们的假设：1）评估PCDH 7- EGFR、IL 6-IL 6 R和CCL 5-CCR 5旁分泌信号传导在使用EGFR、IL 6-IL 6 R和CCL 5-CCR 5旁分泌信号传导的获得和丧失的BM小鼠模型中的表达 功能和药理学方法; 2）评估 星形胶质细胞分泌的蛋白质在改变早期BM中的BBB和小胶质细胞/巨噬细胞的功能; 3） 进一步以癌症类型特异性方式表征时间上进化的星形胶质细胞-BM细胞串扰。 本研究的创新之处在于：（1）本研究整合了两种方法的知识和方法 神经科学和癌症，以确定和表征促转移和抗转移星形胶质细胞分子 机制，它们在疾病进展过程中的演变，以及它们的操纵，以提供有价值的 针对星形胶质细胞与癌细胞相互作用的手段。(ii)这项研究利用了强大的预测模型， 细胞间通讯（CCCExplorer）研究和描绘肿瘤-星形胶质细胞的复杂网络 以公正的方式进行全面的互动。(iii)这项研究将探讨是否有任何具体的 关于BM期间的哪个时间点可能代表调节的最有效点的治疗窗 并瞄准恶性星形细胞肿瘤的串扰。(iv)考虑到星形胶质细胞对BM的强烈反应， 在脑定植过程中，分泌分子的鉴定可能代表脑定植的假定生物标志物。 早期诊断或治疗反应。(v)这项研究产生的数据将形成一个非凡的知识库 不同的大脑疾病之间的比较分析，以询问共同和不同方面的问题， 星形胶质细胞生物学在不同的情况下，以及评估潜在的新的治疗策略， 药物再利用和组合。我们的研究结果将提供一个范式转变， 了解BM的病理学，同时对未来的治疗产生重大影响。 毁灭性的疾病

As treatment outcomes of primary or systemic cancer sites improve, the clinical importance of brain metastasis (BM) is growing. Twenty-four to 45 percent of all cancer patients develop BM, the majority from lung, breast or melanoma primary cancers, but few patients with BM live longer than a year, and BM constitutes 20% of annual cancer deaths. Ironically, recent advancement in chemotherapy has further increased the incidence of BM because most therapeutic agents cannot effectively penetrate the blood-brain barrier (BBB) and tumor cells find the brain as a sanctuary. Therefore, it is of paramount importance to have a deeper understanding of mechanisms that promote BM growth, which could be specifically leveraged to overcome current limitations in therapy. As opposed to the molecular mechanisms involving cancer cell–host interactions shared by multiple cancer types that result in organ specific metastasis, a highly distinct set of structural, anatomic, physiologic and molecular factors regulate metastasis to the brain. Astrocytes, the most common glial cell comprising ~ 50% of all human brain cells, are a well characterized perilesional component of BM and recent discoveries, including ours, provide compelling evidence that molecular crosstalk between astrocytes and cancer cells is integral to BM development. Although seminal findings indicate that interactions with astrocytes occur at both early and late stages of tumor colonization process, our understanding of the reciprocal astrocyte-cancer cell crosstalk is limited. In preliminary studies, we have employed our Cell-Cell Communication Explorer (CCCExplorer), a unique computational modeling tool, in identifying the novel PCDH7-EGFR, IL6-IL6R, and CCL5-CCR5 astrocyte-tumor crosstalk signaling in regulating BM. Based on these observations and in view of the secretory nature of glial cells, we propose here to test the hypothesis that crosstalk with astrocyte-derived secreted factors is critical for tumor cell colonization in the brain. Given that an even more complicated paracrine signaling network may dynamically evolve at different stages of BM development, and the interactions could provide both anti- and pro-metastatic stimuli to cancer cells, we will test our hypothesis through the following aims: 1) to assess therapeutic potential of the PCDH7- EGFR, IL6-IL6R and CCL5-CCR5 paracrine signaling in BM mouse models employing gain and loss of function and pharmacologic approaches in syngeneic mouse and human cancer xenografts; 2) to assess the astrocyte secreted proteins in modifying the function of BBB and microglia/macrophage in early BM; 3) to further characterize the temporally evolved astrocyte-BM cell crosstalks in a cancer type specific fashion. Our study is highly innovative in that (i) this study integrates knowledge and methods from both neuroscience and cancer to identify and characterize pro- and anti-metastatic astrocyte molecular mechanisms, their evolution during disease progression, and their manipulation in order to provide a valuable means of targeting astrocyte-cancer cell interactions. (ii) This study leverages powerful predictive modeling of cell-cell communications (CCCExplorer) to investigate and delineate the complex network of tumor-astrocyte interactions holistically in an unbiased manner. (iii) This study will address whether there is any specific therapeutic window as to which time point during BM might represent the most effective point of modulating and targeting the vicious astrocyte-tumor crosstalk. (iv) Given the strong response of astrocytes to BM during the course of brain colonization, the identification of secreted molecules may represent putative biomarkers of early diagnosis or response to therapy. (v) Data generated in this study would form an extraordinary repository for comparative analyses between different brain disorders to interrogate common and different aspects of astrocyte biology in different scenarios as well as to evaluate the potential new therapeutic strategies such as drug repurposing and combinations. The outcome of our study will provide a paradigm shift in current understanding of the pathology of BM, while achieving a significant impact on future treatments for this devastating disease.