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: 10389114
• 负责人: Sarah C Wang
• 金额: $ 3.54万
• 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/10389114
• 关键词: ANXA5 gene; Adhesions; Adopted; Apoptosis; Apoptotic; Attenuated; Autopsy; Biology; Blood Vessels; Brain; CASP3 gene; Cell Line; Cells; Cicatrix; Clinical; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Data; Dependence; Development; Disease; Drug resistance; 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; 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; cohesion; differential expression; experimental study; field study; imaging platform; in vivo; insight; intravital imaging; melanoma; migration; mortality; mutant; 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 恶性黑色素瘤具有转移到大脑的异常高的希望。在IV期患者中 40-50％将出现临床可检测到的颅内疾病，而在尸检脑转移中可能是 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 通过全身性靶向疗法和免疫疗法改进任务，颅内控制仍然存在 一个重大的挑战。在脑微环境中，主要发现黑色素瘤细胞在A 血管周围的小众将脉管系统“选择”以支持其生存和入侵深处 皮质。虽然这种血管合作生长模式与黑色素瘤的存活不良有关 转移，血管介导的机制知之甚少，这是一个独特的机会 靶向黑色素瘤细胞与内皮之间的内聚相互作用，以预防或治疗大脑 转移。我的初步数据发现了转化生长因子的血管介导的诱导 与黑色素瘤细胞中的β（TGFβ）和血小板衍生的生长因子受体β（PDGFRβ）接触后 脑内皮细胞。此外，此TGFβ-PDGFRβ信号轴可以激活下游PI3K/AKT 当肿瘤抑制磷酸酶Tensin同源物（PTEN）是 丢失的。 PI3K/AKT激活或PTEN的丧失与黑色素瘤大脑的发病机理密切相关 转移但尚未在血管介导的生存或侵袭的背景下探索。那在我的 提案我假设血管介导的TGFβ-PDGFRβ信号传导与 PTEN损失对于大脑微环境中的黑色素瘤细胞侵袭和生存至关重要。 在我的整个建议中，我将生成和利用与TGFβ，PDGFRβ或PTEN改变的同基因线 （或变化的组合），并将通过各种In研究其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。成功完成这项工作 将揭示黑色素瘤脑转移中TGFβ，PDGFRβ和PTEN的新型血管衍生作用；这会 为开发与破坏与凝聚力相互作用的治疗剂提供关键见解和理由 脑内皮并利用血管周围脑生态位的生存优势。完成我的 目标，我已经组建了一个由潜水员但完整的学习领域组成的导师团队，以支持我 提议。这些包括Drs。安德鲁·达德利（Andrew Dudley）（肿瘤微环境/血管生成），craig slingluff （黑色素瘤临床科学家），Camilo Fadul（脑转移临床），詹姆斯·曼德尔（James Mandell）（神经病理学家）， Roger Abounader（Pten Biology and Brain Cancers），David Kashatus（开发的合作者 大脑中的血管合作的定量成像平台）和Hui Zong（高级成像和啮齿动物 大脑癌的模型）。