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。尽管有改进，但 手术、放疗和化疗的中位生存期仍为18-24个月。胶质瘤是浸润性的 肿瘤会侵犯周围的正常脑组织，因此不可能进行完全手术切除。肿瘤细胞 手术后残留的肿瘤最终会导致肿瘤复发，导致患者死亡。胶原蛋白 在乳腺癌、前列腺癌和胰腺肿瘤等多种肿瘤的发展过程中起着重要作用。它的 然而，对其在胶质瘤中的作用仍知之甚少。细胞、分子和功能的初步数据 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来自人类原发疾病的TCGA和GRAS数据的分析支持 复发的胶质瘤表明中位生存期与Col1A1水平呈负相关。人类 实验性小鼠胶质瘤含有细长的间充质样瘤细胞束，代表 肿瘤侵袭边界和肿瘤核心内的集体运动区； 在临床前小鼠模型和人类患者中，这些区域与较差的预后有关。ScRNAseq 随后，RNAScope发现了两种表达显著水平的Col1A1的细胞。高COL1A1- 表达细胞位于血管周围基质细胞内，胶质瘤细胞本身表达较低，但 大量的Col1A1。使用激光显微解剖间充质样结构，然后 RNAseq我们证实，集体运动区富含间充质标志物，如COL1A1 和ACTA2。这些实验预测了Col1A1在肿瘤进展中的重要作用。这是被检查过的 通过在基因工程小鼠胶质瘤模型的诱导过程中表达Col1A1的shRNA (GEM)使用我们的睡美人系统。事实上，从早期的肿瘤细胞中敲除Col1A1 GEMM提高细长间充质样瘤的中位生存期和消除束状面积 细胞；然而，肿瘤仍在发展，动物死亡，血管周围COL1A1的表达 留了下来。这增加了COL1A1在血管周围基质细胞中的表达在 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 已建立的肿瘤内的细胞将延缓肿瘤的进展并减少集体运动。因此，有一个 迫切需要从机制上了解Col1A1如何促进胶质瘤的进展和侵袭。 我们的总体目标是确定表达Col1A1的每个细胞隔室在胶质瘤中的作用 生长和侵袭(AIM-1)，COL1A1在胶质瘤细胞间表达的功能作用 动力学(AIM 2)，以及胶原蛋白及其受体在胶质瘤放射反应中的作用(AIM 3)。 我们的中心假设是，表达Col1A1的细胞在胶质瘤的进展和 阻断Col1A1和/或其受体可发现治疗GBM的新靶点。