Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors

随着原发或全身癌症部位治疗结果的改善，脑转移的临床重要性 (BM)正在增长。24%到45%的癌症患者会患上BM，大多数来自肺癌、乳腺癌或 黑色素瘤原发癌症，但很少有BM患者的寿命超过一年，BM占20% 每年死于癌症的人数。具有讽刺意味的是，最近化疗的进步进一步增加了 因为大多数治疗药物不能有效地穿透血脑屏障(BBB)和肿瘤 细胞发现大脑是一个避难所。因此，最重要的是要加深对 促进BM增长的机制，可以特别利用这一机制来克服目前在 心理治疗。 与多种癌症共享的涉及癌细胞-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，一套高度不同的结构、解剖、生理和 分子因素调节脑部转移。星形胶质细胞，最常见的胶质细胞，约占50% 所有的人类脑细胞都是BM的一种典型的病变周围成分，最近的发现包括 我们的，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 黑石发展。尽管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 在肿瘤定植过程的后期，我们对星形胶质细胞-癌细胞相互串扰的理解是 有限的。在初步研究中，我们使用了我们的细胞-细胞通讯浏览器(CCCExplorer)，一个 独特的计算建模工具，用于识别新的PCDH7-EGFR、IL6-IL6R和CCL5-CCR5 星形胶质细胞-肿瘤信号在调节骨髓中的串扰。基于这些观察，并鉴于 胶质细胞的本质，我们建议在这里检验与星形胶质细胞来源的串扰分泌的假设 这些因素对肿瘤细胞在大脑中的定植至关重要。 假设更复杂的旁分泌信令网络可能以不同的速度动态演变 BM发展的不同阶段，相互作用可以为癌症提供抗转移和促转移刺激 细胞，我们将通过以下目标验证我们的假设：1)评估PCDH7的治疗潜力- EGFR、IL6-IL6R和CCL5-CCR5旁分泌信号在BM小鼠模型中的得失 同基因小鼠和人肿瘤移植瘤的功能和药理学方法；2)评估 BM早期星形胶质细胞分泌蛋白对血脑屏障和小胶质细胞/巨噬细胞功能的调节作用 进一步表征时间进化的星形胶质细胞-骨髓细胞以癌症类型特定的方式进行的串扰。 本研究的创新之处在于：(1)本研究综合了两方面的知识和方法 神经科学和癌症识别和表征促转移和抗转移的星形胶质细胞分子 机制，它们在疾病发展过程中的演变，以及它们的操纵，以提供有价值的 靶向星形胶质细胞-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-细胞通讯(CCCExplorer)研究和描绘肿瘤-星形胶质细胞的复杂网络 以不偏不倚的方式进行整体互动。(三)这项研究将探讨是否有任何具体的 BM期间哪个时间点可能代表最有效的调节时间点的治疗窗口 并瞄准恶性星形细胞-肿瘤的串音。(Iv)鉴于星形胶质细胞对骨髓的强烈反应 在脑定植过程中，分泌分子的鉴定可能代表着推测的生物标志物 早期诊断或对治疗的反应。(5)本研究中产生的数据将形成一个特别的储存库 对于不同大脑疾病之间的比较分析，以询问共同和不同的方面 不同情况下的星形胶质细胞生物学以及评估潜在的新治疗策略，如 药物再利用和组合。我们的研究结果将提供当前的范式转变 了解BM的病理，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.