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).

项目总结/摘要 恶性黑色素瘤有异常高的倾向转移到大脑;在第四阶段的患者 40-50%的患者会出现临床上可检测到的颅内疾病，而尸检时脑转移可以被发现。 在70%以上的患者中发现。此外，黑色素瘤脑转移是预后不良的标志， 尽管全身靶向治疗和免疫治疗有所改善，但颅内控制仍然存在 一个重大的挑战。在大脑微环境中，黑色素瘤细胞主要存在于 血管周围的生态位，在那里他们“增选”脉管系统，以支持他们的生存和入侵深入到 皮层虽然这种血管共选择性生长模式与黑色素瘤的生存率低有关， 转移，血管介导的机制知之甚少，代表了一个独特的机会， 靶向黑色素瘤细胞和内皮细胞之间的粘附相互作用， 转移我的初步数据揭示了血管介导的转化生长因子诱导 在黑色素瘤细胞中， 脑内皮细胞此外，TGFβ-PDGFRβ信号轴可以激活下游PI 3 K/AKT， 当肿瘤抑制蛋白磷酸酶张力蛋白同源物（PTEN）被激活时， 迷路了PI 3 K/AKT激活或PTEN缺失与脑黑色素瘤的发病机制密切相关 转移，但尚未在血管介导的存活或侵袭的背景下进行探索。因此，在我 建议我假设血管介导的TGFβ-PDGFRβ信号传导的诱导与 PTEN缺失对于黑色素瘤细胞在脑微环境中的侵袭和存活是重要的。 在我的整个提案中，我将产生和利用TGFβ，PDGFRβ或PTEN改变的等基因系， (or改变的组合），并将通过各种方法研究它们对迁移和凋亡的影响。 体外共培养系统、离体脑切片和体内颅内模型。圆满完成这项工作 将揭示TGFβ、PDGFRβ和PTEN在黑色素瘤脑转移中的新的血管源性作用;这将 提供了重要的见解和理论基础的治疗，破坏凝聚力的相互作用， 脑内皮，并利用血管周围脑生态位的生存优势。完成我 为了实现目标，我组建了一个导师团队，他们拥有不同但互补的研究领域，以支持我的工作。 提议其中包括安德鲁达德利博士（肿瘤微环境/血管生成），克雷格Slingluff （黑色素瘤临床医生-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），大卫卡沙图斯（合作者，开发 定量成像平台的血管co-option在大脑中），和惠宗（先进的成像和啮齿动物 脑癌模型）。