Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors

星形胶质细胞-肿瘤串扰调节脑转移瘤的系统鉴定

• 批准号: 10337313
• 负责人: STEPHEN TC WONG
• 金额: $ 36.2万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337313
• 关键词: Address; Anatomy; Animals; Antibody Therapy; Apoptosis; Astrocytes; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Pathology; Breast; Breast Melanoma; CCR5 gene; Cancer Model; Cancer Patient; Cell Communication; Cell model; Cells; Central Nervous System Agents; Cessation of life; Clinical; Coculture Techniques; Complex; Computer Models; Data; Development; Disease; Disease Progression; Drug Combinations; Early Diagnosis; Epidermal Growth Factor Receptor; Evolution; Extravasation; Future; Growth; Human; I Kappa B-Alpha; IL6 gene; In Vitro; Incidence; Knowledge; Lung; MAP Kinase Gene; Malignant Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Methods; Microglia; Molecular; Mus; Nature; Neoplasm Metastasis; Neuroglia; Neurosciences; Organ; Outcome; Paracrine Communication; Pathogenesis; Patients; Penetration; Pharmacology; Physiological; Process; Proteins; RANTES; Radiation therapy; Seminal; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Agents; Time; Trastuzumab; Treatment outcome; Tumor stage; Tumor-Secreted Protein; Xenograft procedure; base; blood-brain barrier function; brain cell; brain tissue; cancer cell; cancer recurrence; cancer site; cancer type; chemotherapy; comparative; crizotinib; diagnostic biomarker; drug repurposing; early detection biomarkers; improved; in vivo; innovation; kinase inhibitor; loss of function; macrophage; melanoma; mouse model; multiplexed imaging; neoplastic cell; neurosurgery; novel; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; predictive modeling; primary outcome; repository; response; small molecule inhibitor; tool; transcriptome sequencing; treatment response; tumor

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.

随着原发性或全身性癌症部位的治疗结果，脑转移的临床重要性 （BM）正在增长。 黑色素瘤初级癌症，但BM患者的寿命很少超过一年，而BM征兵的寿命为20％ 具有讽刺意味的是，每年的癌症死亡。 因为大多数治疗剂无法有效地穿透血液堵嘴（BBB）和肿瘤 细胞认为大脑是一种宗教信仰。 促进BM增长的机制，可以利用这些机制来克服货币限制 治疗。 与分子机制相反，癌细胞 - 由多个癌症共享的宿主相互作用 导致器官特异性转移的类型，一组高度不同的结构，解剖学，生理和 分子因子调节大脑的转移。 所有人类脑细胞，都是BM和最近发现的核心成分，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不可或缺的 BM开发。 肿瘤定植过程的后期阶段，我们对倒数星形胶质细胞cyrostalk的理解是 在预序研究中，我们已经重新建立 独特的计算建模工具 根据观测值和分泌物的观察，星形胶质细胞串扰信号传导。 神经胶质细胞的性质，我们建议检验以星形胶质细胞衍生的crostalk的假设 因素对于大脑中的肿瘤细胞定植至关重要。 鉴于一个更复杂的旁分泌信号网络我在不同的情况下动态演变 BM发育的阶段，相互作用可以为癌症提供抗 - 和促刺激 细胞，我们将通过以下目的测试我们的假设：1）评估PCDDH7-- BM小鼠模型中的EGFR，IL6-IL6R和CCL5-CCR5旁分泌信号传导采用增益和损失 合成小鼠和人类癌的功能和药理方法 星形胶质细胞分泌的蛋白质在早期BM中修改BBB和小胶质细胞/巨噬细胞的功能； 进一步以癌症类型的方式进一步表征了临时进化的星形胶质细胞-BM细胞crostalks。 我们的研究具有很高的创新性，因为（i）本研究将两者的知识和方法整合在一起 神经科学和癌症，以识别和表征促和抗中转移的星形胶质细胞分子 机制，它们在疾病进展过程中的演变以及其操纵以提供可用的 靶向星形胶质细胞相互作用的手段。 细胞电池通信（CCCEXPLORER）调查和描述肿瘤 - 胃细胞的复杂网络 以公正的方式整体上的互动。 治疗窗口在调制的最有效点期间的时间点 并针对恶性星形胶质细胞曲线。 大脑定植的过程，分泌分子的鉴定可能会压抑 早期诊断或对治疗的反应。 为了在不同的脑疾病之间进行比较分析，以询问常见和不同方面 在不同情况下，星形胶质细胞生物学评估了潜在的新治疗策略，例如 药物重新利用和组合。 了解BM的病理，同时对此产生重大影响 毁灭性疾病。