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: 10539332
• 负责人: Pedro R Lowenstein
• 金额: $ 51.54万
• 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/10539332
• 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; Gene Deletion; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; Immune; Invaded; Lasers; Lesion; Malignant Glioma; Mammary Neoplasms; Mediating; Mesenchymal; Microdissection; Modeling; Molecular; Motion; Mus; Operative Surgical Procedures; Outcome; Patients; Pattern; Pericytes; Play; Prognosis; Prostatic Neoplasms; Radiation; Radiation therapy; Recurrence; Recurrent tumor; 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; improved; in vivo; inhibitor; knock-down; mouse model; neoplastic cell; neuropathology; new therapeutic target; pancreatic neoplasm; pharmacologic; 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袭性和致命性的。尽管有所改进 手术、放疗和化疗，中位生存期仍约为 18-24 个月。胶质瘤是浸润性的 肿瘤侵入周围正常脑组织，使得手术无法完全切除。肿瘤细胞 手术后残留的残留物最终会导致肿瘤复发，导致患者死亡。胶原 在乳腺肿瘤、前列腺肿瘤、胰腺肿瘤等多种肿瘤的进展中发挥着重要作用。它是 然而，其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已 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 GLASS、人类初级数据的分析的支持 和复发性神经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，代表 肿瘤浸润边界和肿瘤核心内的集体运动区域；密度增加 这些区域与临床前小鼠模型和人类患者的较差预后相关。单链RNA测序 随后 RNAscope 鉴定了两种表达显着水平 Col1A1 的细胞。高Col1A1- 表达细胞存在于血管周围基质细胞内，神经胶质瘤细胞本身表达较低，但 Col1A1 的显着水平。使用激光显微切割间质样结构，然后 RNAseq 我们证实集体运动区域富含间充质标记，例如 Col1A1 和 ACTA2。这些实验预测 Col1A1 在肿瘤进展中的重要作用。对此进行了检查 通过在基因工程小鼠神经胶质瘤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，Col1A1 从早期的肿瘤细胞中被敲除 GEMM 提高了中位生存率并消除了细长间充质样肿瘤的束区域 细胞；然而，肿瘤仍在进展，动物变得濒临死亡，并且 Col1A1 的血管周围表达 留下来了。这提出了血管周围基质细胞中 Col1A1 的表达发挥重要作用的可能性。 在神经胶质瘤进展中的作用。目前尚不清楚 Col1A1 是否因肿瘤或血管周围基质而被耗尽 已形成肿瘤内的细胞将延缓肿瘤进展并减少集体运动。因此，有一个 迫切需要了解 Col1A1 如何促进神经胶质瘤进展和侵袭的机制。 我们的总体目标是确定表达 Col1A1 的每个细胞区室在神经胶质瘤中的作用 生长和侵袭 (AIM 1)，Col1A1 表达在神经胶质瘤任一细胞区室中的功能作用 动力学（AIM 2），以及胶原蛋白及其受体对神经胶质瘤放射反应的作用（AIM 3）。 我们的中心假设是 Col1A1 表达细胞在神经胶质瘤进展和 侵袭以及阻断 Col1A1 和/或其受体可能会发现 GBM 的新治疗靶点。