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.

摘要