The role of collagen and its signaling mechanisms in glioma progression and invasion.

胶原蛋白及其信号传导机制在神经胶质瘤进展和侵袭中的作用。

• 批准号: 10387976
• 负责人: Pedro R Lowenstein
• 金额: $ 52.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387976
• 关键词: Animals; Area; Blood Vessels; Brain; Brain Neoplasms; COL1A1 gene; Cell Compartmentation; Cells; Collagen; Collagen Fiber; Collagen Receptors; DDR1 gene; Data; Excision; Fascicle; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; Immune; Invaded; Lasers; Lead; Lesion; Malignant Glioma; Mammary Neoplasms; Mediating; Mesenchymal; Microdissection; Modeling; Molecular; Motion; Mus; Operative Surgical Procedures; Outcome; Patients; Pattern; Pericytes; Pharmacology; Play; Prognosis; Prostatic Neoplasms; Radiation; Radiation therapy; Recurrence; Role; Signal Transduction; Sleeping Beauty; Stromal Cells; Structure; System; The Cancer Genome Atlas; Transgenic Organisms; Tumor Cell Invasion; brain tissue; cell stroma; cell type; chemotherapy; density; evidence base; experimental study; human data; in vivo; inhibitor; knock-down; mouse model; neoplastic cell; neuropathology; new therapeutic target; pancreatic neoplasm; pre-clinical; preservation; receptor; resistance mechanism; response; small hairpin RNA; standard of care; temozolomide; therapeutic target; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Abstract Malignant gliomas continue to be the most aggressive and lethal of all brain tumors. In spite of improvements in surgery, radiotherapy, and chemotherapy, median survival remains ~18-24 months. Gliomas are infiltrative tumors that invade the surrounding normal brain tissue making total surgical resection impossible. Tumor cells that remain after surgery eventually lead to tumor recurrence, causing the demise of the patients. Collagen plays an important role in the progression of various tumors such as breast, prostate and pancreatic tumors. Its role in gliomas, however, remains poorly understood. Cellular, molecular and functional preliminary data have identified Collagen1A1 (Col1A1) as an important determinant of tumor progression and invasion. An important role of Col1A1 in patient survival is supported by the analysis of TCGA, and GLASS, data from human primary and recurrent gliomas that indicate that median survival is inversely correlated with levels of Col1A1. Human and experimental mouse gliomas contain fascicles of elongated mesenchymal-like tumor cells that represent areas of collective motion within the tumor invasive border, and the tumor core; an increase in the density of these areas is associated with worse prognosis in preclinical mouse models and in human patients. scRNAseq followed by RNAscope identified two types of cells that express significant levels of Col1A1. High Col1A1- expressing cells are found within perivascular stroma cells, and glioma cells themselves express lower, but significant levels of Col1A1. Using laser-microdissection of the mesenchymal-like structures followed by RNAseq we confirmed that areas of collective motion are enriched in mesenchymal markers such as Col1A1 and ACTA2. These experiments predict an important role for Col1A1 in tumor progression. This was examined by expressing a shRNA for Col1A1 during the induction of genetically engineered mouse models of glioma (GEMMs) using our Sleeping Beauty system. Indeed, knockdown of Col1A1 from tumor cells from incipient GEMMs increased median survival and eliminated areas of fascicles of elongated mesenchymal-like tumor cells; however, tumors still progressed, animals became moribund, and perivascular expression of Col1A1 remained. This raises the possibility that expression of Col1A1 in perivascular stromal cells plays an important role in glioma progression. What is not known is if Col1A1 depletion from either tumor or perivascular stromal cells within established tumors will delay tumor progression and reduce collective motion. Thus, there is a critical need for a mechanistic understanding of how Col1A1 contributes to glioma progression and invasion. Our overall objectives are to establish the role of each cellular compartment that expresses Col1A1 on glioma growth and invasion (AIM 1), the functional role of Col1A1 expression in either cellular compartment on glioma dynamics (AIM 2), and the role of collagen and its receptors on the response of gliomas to radiation (AIM 3). Our central hypothesis is that Col1A1 expressing cells play a significant role in glioma progression and invasion and that blocking Col1A1 and/or its receptors could uncover a novel therapeutic target for GBM.

摘要 恶性神经胶质瘤仍然是所有脑肿瘤中最具侵袭性和致命性的。尽管有改善， 手术、放疗和化疗，中位生存期仍为18 - 24个月。胶质瘤是浸润性的 肿瘤侵入周围的正常脑组织，使手术切除成为不可能。肿瘤细胞 手术后残留的肿瘤最终导致肿瘤复发，导致患者死亡。胶原 在各种肿瘤如乳腺癌、前列腺癌和胰腺癌的进展中起重要作用。其 然而，在神经胶质瘤中的作用仍然知之甚少。细胞、分子和功能的初步数据 发现胶原蛋白1A1（Col1A1）是肿瘤进展和侵袭的重要决定因素。一个重要 Col1A1在患者生存中的作用得到了TCGA和GLASS分析的支持，这些数据来自人类原发性肝癌。 和复发性胶质瘤，表明中位生存期与Col1A1水平呈负相关。人类 实验小鼠神经胶质瘤含有细长的间充质样肿瘤细胞束， 肿瘤浸润边界和肿瘤核心内的集体运动区域; 这些区域与临床前小鼠模型和人类患者中的较差预后相关。scRNAseq 随后通过RNAscope鉴定出两种类型的细胞表达显著水平的Col1A1。高Col1A1- 在血管周围基质细胞中发现表达细胞，胶质瘤细胞本身表达较低，但 高水平的Col1A1。使用激光显微切割间充质样结构， 我们证实集体运动区域富含间充质标记物，如Col1A1 ACTA2。这些实验预测了Col1A1在肿瘤进展中的重要作用。这是经过检查的 通过在神经胶质瘤基因工程小鼠模型的诱导过程中表达Col1A1的shRNA， （GEMM）使用我们的睡美人系统。事实上，从肿瘤细胞中敲除Col1A1， GEMM增加了中位生存率，消除了细长间叶样肿瘤的束区 然而，肿瘤仍然进展，动物变得濒死，并且血管周围表达Col1A1 剩下这增加了血管周围基质细胞中Col1A1的表达在血管周围基质细胞中起重要作用的可能性。 在胶质瘤进展中的作用。目前尚不清楚的是，Col1A1是否从肿瘤或血管周围间质中耗尽 已形成的肿瘤内的细胞将延迟肿瘤进展并减少集体运动。由此可见，有一 迫切需要了解Col1A1如何促进胶质瘤进展和侵袭的机制。 我们的总体目标是确定表达Col1A1的每个细胞区室在胶质瘤中的作用。 生长和侵袭（AIM 1），Col1A1表达在胶质瘤细胞中的功能作用 动力学（AIM 2）和胶原及其受体对胶质瘤放射反应的作用（AIM 3）。 我们的中心假设是表达Col1A1的细胞在胶质瘤进展中起重要作用， 侵袭和阻断Col1A1和/或其受体可能揭示GBM新治疗靶点。