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.

抽象的 恶性神经胶质瘤仍然是所有脑肿瘤中最具侵略性和致命性的。尽管有改善 手术，放疗和化疗，中位生存期仍然约18-24个月。神经胶质瘤具有浸润性 侵袭周围正常脑组织的肿瘤使总体手术切除不可能。肿瘤细胞 手术后仍然会导致肿瘤复发，从而导致患者的灭亡。胶原 在乳腺癌，前列腺和胰腺肿瘤等各种肿瘤的进展中起重要作用。它是 然而，在神经胶质瘤中的作用仍然知之甚少。细胞，分子和功能初步数据具有 确定胶原蛋白1a1（COL1A1）是肿瘤进展和侵袭的重要决定因素。一个重要的 Col1a1在患者生存中的作用得到了TCGA和玻璃的分析，来自人类主要的数据 复发性神经膜瘤表明中位生存期与COL1A1水平成反比。人类 和实验小鼠神经胶质瘤包含伸长的间充质样细胞的束，代表 肿瘤侵入性边界内的集体运动区域和肿瘤核心；密度的增加 这些区域与临床前小鼠模型和人类患者的预后较差有关。 scrnaseq 然后是rnascope鉴定出表达显着水平COL1A1的两种类型的细胞。高col1a1- 在血管内基质细胞中发现表达细胞，胶质瘤细胞本身表达较低，但 Col1a1的显着水平。使用间充质样结构的激光 - 微截断，然后 RNASEQ我们确认集体运动领域富含在诸如Col1a1之类的间充质标记中 和acta2。这些实验预测了COL1A1在肿瘤进展中的重要作用。对此进行了检查 通过在诱导基因工程小鼠胶质瘤模型的过程中表达COL1A1的shRNA （宝石）使用我们的睡美人系统。实际上，从肿瘤细胞中敲低Col1a1 宝石增加了中位生存期，并消除了细长间充质样肿瘤束的区域 细胞；然而，肿瘤仍在发展，动物变成了垂死，Col1a1的血管周围表达 留下来。这增加了Col1a1在血管周围基质细胞中的表达的可能性 在神经胶质瘤进展中的作用。尚不清楚的是COL1A1是否从肿瘤或血管周间耗尽 已建立的肿瘤内的细胞会延迟肿瘤的进展并减少集体运动。因此，有一个 对COL1A1如何促进神经胶质瘤进展和侵袭的机械理解的批判性需求。 我们的总体目标是确定表达COL1A1在神经胶质瘤上的每个细胞室的作用 生长和侵袭（AIM 1），Col1a1表达在任何细胞区室上的功能作用 动力学（AIM 2），以及胶原蛋白及其受体对神经胶质瘤对辐射的反应的作用（AIM 3）。 我们的中心假设是表达细胞的Col1a1在神经胶质瘤进展中起重要作用 入侵以及阻断COL1A1和/或其受体可以发现GBM的新型治疗靶标。