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。
基本信息
- 批准号:10387976
- 负责人:
- 金额:$ 52.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AnimalsAreaBlood VesselsBrainBrain NeoplasmsCOL1A1 geneCell CompartmentationCellsCollagenCollagen FiberCollagen ReceptorsDDR1 geneDataExcisionFascicleGeneticGenetically Engineered MouseGlioblastomaGliomaGoalsGrowthHumanImmuneInvadedLasersLeadLesionMalignant GliomaMammary NeoplasmsMediatingMesenchymalMicrodissectionModelingMolecularMotionMusOperative Surgical ProceduresOutcomePatientsPatternPericytesPharmacologyPlayPrognosisProstatic NeoplasmsRadiationRadiation therapyRecurrenceRoleSignal TransductionSleeping BeautyStromal CellsStructureSystemThe Cancer Genome AtlasTransgenic OrganismsTumor Cell Invasionbrain tissuecell stromacell typechemotherapydensityevidence baseexperimental studyhuman datain vivoinhibitorknock-downmouse modelneoplastic cellneuropathologynew therapeutic targetpancreatic neoplasmpre-clinicalpreservationreceptorresistance mechanismresponsesmall hairpin RNAstandard of caretemozolomidetherapeutic targettranscriptome sequencingtumortumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Pedro R Lowenstein其他文献
Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial
原发性成人高级别胶质瘤的联合细胞毒性和免疫刺激基因治疗:一项 1 期、首次人体试验
- DOI:
10.1016/s1470-2045(23)00347-9 - 发表时间:
2023-09-01 - 期刊:
- 影响因子:35.900
- 作者:
Yoshie Umemura;Daniel Orringer;Larry Junck;Maria L Varela;Molly E J West;Syed M Faisal;Andrea Comba;Jason Heth;Oren Sagher;Denise Leung;Aaron Mammoser;Shawn Hervey-Jumper;Daniel Zamler;Viveka N Yadav;Patrick Dunn;Wajd Al-Holou;Todd Hollon;Michelle M Kim;Daniel R Wahl;Sandra Camelo-Piragua;Pedro R Lowenstein - 通讯作者:
Pedro R Lowenstein
Crossing the Rubicon
破釜沉舟
- DOI:
10.1038/nbt0109-42 - 发表时间:
2009-01-01 - 期刊:
- 影响因子:41.700
- 作者:
Pedro R Lowenstein - 通讯作者:
Pedro R Lowenstein
Pedro R Lowenstein的其他文献
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{{ truncateString('Pedro R Lowenstein', 18)}}的其他基金
Role of the collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment
胶原蛋白受体LAIR-1在神经胶质瘤进展和肿瘤免疫微环境中的作用
- 批准号:
10462939 - 财政年份:2022
- 资助金额:
$ 52.9万 - 项目类别:
Role of the collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment
胶原蛋白受体LAIR-1在神经胶质瘤进展和肿瘤免疫微环境中的作用
- 批准号:
10581659 - 财政年份:2022
- 资助金额:
$ 52.9万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 52.9万 - 项目类别:
Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms
恶性脑肿瘤的神经免疫学:先天机制
- 批准号:
9215708 - 财政年份:2016
- 资助金额:
$ 52.9万 - 项目类别:
Neuroimmunology of Malignant Brain Tumors: Innate Mechanisms
恶性脑肿瘤的神经免疫学:先天机制
- 批准号:
9115388 - 财政年份:2016
- 资助金额:
$ 52.9万 - 项目类别:
Mechanisms of glioma growth and invasion novel therapeutic strategies
神经胶质瘤生长和侵袭的机制新的治疗策略
- 批准号:
8883736 - 财政年份:2013
- 资助金额:
$ 52.9万 - 项目类别:
Mechanisms of glioma growth and invasion novel therapeutic strategies
神经胶质瘤生长和侵袭的机制新的治疗策略
- 批准号:
9039671 - 财政年份:2013
- 资助金额:
$ 52.9万 - 项目类别:
Mechanisms of glioma growth and invasion novel therapeutic strategies
神经胶质瘤生长和侵袭的机制新的治疗策略
- 批准号:
9250229 - 财政年份:2013
- 资助金额:
$ 52.9万 - 项目类别:
Mechanisms of glioma growth and invasion novel therapeutic strategies
神经胶质瘤生长和侵袭的机制新的治疗策略
- 批准号:
8480082 - 财政年份:2013
- 资助金额:
$ 52.9万 - 项目类别:
Inhibiting glioma invasion using targeted nanoparticles
使用靶向纳米粒子抑制神经胶质瘤侵袭
- 批准号:
8573433 - 财政年份:2013
- 资助金额:
$ 52.9万 - 项目类别:
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