Mechanisms of perivascular melanoma dispersal and survival in the brain

血管周围黑色素瘤在大脑中扩散和存活的机制

• 批准号: 10547753
• 负责人: Sarah C Wang
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547753
• 关键词: ANXA5 gene; Adhesions; Adopted; Apoptosis; Apoptotic; Attenuated; Autopsy; Biology; Blood Vessels; Brain; Brain Injuries; CASP3 gene; Cell Death; Cell Line; Cells; Cerebrovascular system; Cicatrix; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Data; Dependence; Development; Disease; Drug resistance; Endothelial Cells; Endothelium; Genes; Goals; Growth; Human; Image; Immunotherapy; In Vitro; Injections; Invaded; Knock-out; Ligands; MAP Kinase Gene; Malignant neoplasm of brain; Measures; Mediating; Melanoma Cell; Mentors; Mesenchymal; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Morphology; Neoplasm Metastasis; Neurons; PI3K/AKT; PTEN gene; Pathogenesis; Pathway interactions; Patients; Pattern; Pericytes; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Process; Production; Prognosis; Proliferating; Resistance; Risk; Rodent Model; Role; Sampling; Scientist; Serum; Signal Transduction; Slice; Stains; Surface; System; Testing; Transforming Growth Factor beta; Travel; Tumor Suppressor Proteins; Up-Regulation; Work; angiogenesis; brain endothelial cell; cancer therapy; cell motility; differential expression; experimental study; field study; imaging platform; improved; in vivo; insight; intravital imaging; melanoma; migration; mortality; mutant; neuronal survival; neuroprotection; new therapeutic target; novel; novel therapeutics; prevent; protective factors; quantitative imaging; single-cell RNA sequencing; targeted treatment; therapeutic development; treatment comparison; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Malignant melanoma has an unusually high propensity to metastasize to the brain; among stage IV patients 40-50% will develop clinically detectable intracranial disease, while on autopsy brain metastases can be detected in over 70% of patients. Additionally, melanoma brain metastases are a marker of poor prognosis and despite improvements with systemic targeted therapies and immunotherapies, intracranial control still remains a significant challenge. In the brain microenvironment, melanoma cells are found predominantly in a perivascular niche where they “co-opt” the vasculature to support their survival and invasion deep into the cortex. While this vascular co-optive growth pattern has been associated with poor survival in melanoma metastasis, vascular-mediated mechanisms are poorly understood and represents a unique opportunity to target the cohesive interactions between melanoma cells and the endothelium to prevent or treat brain metastases. My preliminary data has uncovered a vascular-mediated induction of transforming growth factor beta (TGFβ) and platelet-derived growth factor receptor beta (PDGFRβ) in melanoma cells after contact with brain endothelial cells. Additionally, this TGFβ-PDGFRβ signaling axis can activate the downstream PI3K/AKT pathway, which has sustained activation when the tumor suppressor phosphatase tensin homolog (PTEN) is lost. PI3K/AKT activation or loss of PTEN has been strongly implicated in the pathogenesis of melanoma brain metastases but has not been explored in the context of vascular-mediated survival or invasion. Thus, in my proposal I hypothesize that vascular-mediated induction of TGFβ-PDGFRβ signaling in concert with PTEN loss is important for melanoma cell invasion and survival in the brain microenvironment. Throughout my proposal, I will generate and utilize isogenic lines with alterations in TGFβ, PDGFRβ, or PTEN (or combinations of alterations) and will study their effects on migration and apoptosis through a variety of in vitro co-culture systems, ex vivo brain slice, and in vivo intracranial models. Successful completion of this work will reveal a novel vascular-derived role for TGFβ, PDGFRβ, and PTEN in melanoma brain metastasis; this will provide crucial insights and rationale for the development of therapeutics that disrupt cohesive interactions with the brain endothelium and exploit the survival advantages of the perivascular brain niche. To complete my goals, I have assembled a team of mentors with diverse but complementary fields of study to support my proposal. These include Drs. Andrew Dudley (tumor microenvironment/angiogenesis), Craig Slingluff (melanoma clinician-scientist), Camilo Fadul (brain metastasis clinician), James Mandell (neuropathologist), Roger Abounader (PTEN biology and brain cancers), David Kashatus (collaborator for the development of quantitative imaging platform of vessel co-option in the brain), and Hui Zong (advanced imaging and rodent models of brain cancers).

项目摘要/摘要 恶性黑色素瘤有异常高的脑转移倾向；在IV期患者中 40%-50%的人会发展为临床可检测到的颅内疾病，而在尸检中可能会出现脑转移 在超过70%的患者中检测到。此外，黑色素瘤脑转移是预后不良和 尽管系统性靶向治疗和免疫治疗有所改善，但颅内控制仍然存在。 这是一个巨大的挑战。在大脑微环境中，黑色素瘤细胞主要存在于 在血管周围的利基环境中，它们“选择”血管系统来支持它们的生存和入侵到 大脑皮层。虽然这种血管协同生长模式与黑色素瘤的低存活率有关 转移，血管介导的机制知之甚少，这是一个独特的机会 靶向黑色素瘤细胞和血管内皮细胞之间的粘连相互作用来预防或治疗脑 转移瘤。我的初步数据发现了一种血管介导的转化生长因子的诱导 接触后黑色素瘤细胞中转化生长因子β和血小板衍生生长因子受体β的表达 脑血管内皮细胞。此外，这种转化生长因子β-PDGFRβ信号轴可以激活下游的PI3K/AKT 当肿瘤抑制因子磷酸酶张力蛋白同源(PTEN)被 迷路了。PI3K/AKT激活或缺失PTEN与黑色素瘤的发病机制密切相关 转移，但还没有在血管介导的生存或侵袭的背景下进行探索。因此，在我的 建议I假设血管介导的转化生长因子β-PDGFFRβ信号的诱导与 PTEN缺失对黑色素瘤细胞在脑微环境中的侵袭和生存具有重要意义。 在我的整个计划中，我将产生和利用转化生长因子β、PDGFFRβ或PTEN改变的等基因系 (或改变的组合)，并将通过不同的途径研究它们对迁移和细胞凋亡的影响。 体外共培养系统，体外脑片，体内颅内模型。圆满完成这项工作 将揭示转化生长因子β、PDGFFRβ和PTEN在黑色素瘤脑转移中的新的血管衍生作用；这将 提供重要的洞察力和理论基础，以开发破坏凝聚力与 脑血管内皮细胞和发挥血管周围脑利基的生存优势。要完成我的 目标，我已经组建了一个导师团队，他们的研究领域各不相同，但相互补充，以支持我的 求婚。这些人包括安德鲁·达德利博士(肿瘤微环境/血管生成)、克雷格·斯林格勒夫 (黑色素瘤临床医生兼科学家)，Camilo Fadul(脑转移临床医生)，James Mandell(神经病理学家)， Roger Abounader(PTEN生物学和脑癌)，David Kashatus(开发 大脑血管选择性定量成像平台)和慧宗(高级成像和啮齿动物 脑癌模型)。